PMID- 27617487 TI - Copper-Catalyzed Decarboxylative Atom Transfer Radical Addition of Iododifluoroacetate to Alkynyl Carboxylic Acids. AB - The first example of copper-catalyzed decarboxylative atom transfer radical addition of alkynyl carboxylic acids has been developed with a readily available fluoroalkyl halide. This novel protocol has demonstrated a unique difunctionalization of nonterminal alkynes with a broad substrate scope and excellent functional-group tolerance. Mechanistic investigations revealed that the catalytic cycle was initiated by the attack of a difluoroalkyl radical to an in situ generated alkynylcopper species. PMID- 27617488 TI - Copper-Catalyzed Aerobic Cascade Oxidative Coupling/Cyclization for the Construction of 1,4-Dihydropyridine Derivatives. AB - An efficient copper-catalyzed cascade cyclization reaction for the preparation of polysubstituted 1,4-dihydropyridines between N-arylglycine esters and 1,3 dicarbonyl compounds using molecular oxygen as the terminal oxidant has been described. Various N-arylglycine esters 1 and 1,3-dicarbonyl compounds 2 were able to undergo the cascade reaction smoothly to afford the desired products 3 in satisfactory yields. The cascade reaction has the advantages of good functional group tolerance and mild reaction conditions. A possible mechanism has also been proposed on the basis of control experiments. PMID- 27617489 TI - Aptamer-Based Microfluidic Electrochemical Biosensor for Monitoring Cell-Secreted Trace Cardiac Biomarkers. AB - Continual monitoring of secreted biomarkers from organ-on-a-chip models is desired to understand their responses to drug exposure in a noninvasive manner. To achieve this goal, analytical methods capable of monitoring trace amounts of secreted biomarkers are of particular interest. However, a majority of existing biosensing techniques suffer from limited sensitivity, selectivity, stability, and require large working volumes, especially when cell culture medium is involved, which usually contains a plethora of nonspecific binding proteins and interfering compounds. Hence, novel analytical platforms are needed to provide noninvasive, accurate information on the status of organoids at low working volumes. Here, we report a novel microfluidic aptamer-based electrochemical biosensing platform for monitoring damage to cardiac organoids. The system is scalable, low-cost, and compatible with microfluidic platforms easing its integration with microfluidic bioreactors. To create the creatine kinase (CK)-MB biosensor, the microelectrode was functionalized with aptamers that are specific to CK-MB biomarker secreted from a damaged cardiac tissue. Compared to antibody based sensors, the proposed aptamer-based system was highly sensitive, selective, and stable. The performance of the sensors was assessed using a heart-on-a-chip system constructed from human embryonic stem cell-derived cardiomyocytes following exposure to a cardiotoxic drug, doxorubicin. The aptamer-based biosensor was capable of measuring trace amounts of CK-MB secreted by the cardiac organoids upon drug treatments in a dose-dependent manner, which was in agreement with the beating behavior and cell viability analyses. We believe that, our microfluidic electrochemical biosensor using aptamer-based capture mechanism will find widespread applications in integration with organ-on-a-chip platforms for in situ detection of biomarkers at low abundance and high sensitivity. PMID- 27617490 TI - Kinetic Isotope Effects as a Probe for the Protonolysis Mechanism of Alkylmetal Complexes: VTST/MT Calculations Based on DFT Potential Energy Surfaces. AB - Protonolysis by platinum or palladium complexes has been extensively studied because it is the microscopic reverse of the C-H bond activation reaction. The protonolysis of (COD)PtIIMe2, which exhibits abnormally large kinetic isotope effects (KIEs), is proposed to occur via a concerted pathway (SE2 mechanism) with large tunneling. However, further investigation of KIEs for the protonolysis of ZnMe2 and others led to a conclusion that there is no noticeable correlation between the mechanism and magnitude of KIE. In this study, we demonstrated that variational transition state theory including multidimensional tunneling (VTST/MT) could accurately predict KIEs and Arrhenius parameters of the protonolysis of alkylmetal complexes based on the potential energy surfaces generated by density functional theory. The predicted KIEs, EaD - EaH values, and AH/AD ratios for the protonolysis of (COD)PtIIMe2 and ZnIIMe2 by TFA agreed very well with experimental values. The protonolysis of ZnMe2 with the concerted pathway has a very flat potential energy surface, which produces a very small tunneling effect and therefore a small KIE. The predicted KIE for the stepwise protonolysis (SE(ox) mechanism) of (COD)PtIIMe2 was much smaller than that of the concerted pathway, but greater than the KIE of the concerted protonolysis of ZnMe2. A large KIE, which entails a significant tunneling effect, could be used as an experimental probe of the concerted pathway. However, a normal or small KIE should not be used as an indicator of the stepwise mechanism, and the interplay between experiments and reliable theory including tunneling would be essential to uncover the mechanism correctly. PMID- 27617491 TI - Utility of Double Inversion Recovery Sequences in MRI. AB - Investigators from the Mayo Clinic, Rochester Minnesota investigated the utility of three-dimensional (3D) double inversion recovery (DIR) sequences in magnetic resonance imaging (MRI) detection of focal cortical dysplasia (FCD) in children and young adults with epilepsy. PMID- 27617492 TI - Isolation of the Novel Chiral Insecticide Paichongding (IPP) Degrading Strains and Biodegradation Pathways of RR/SS-IPP and SR/RS-IPP in an Aqueous System. AB - Chiral insecticide paichongding (IPP) is a member of cis-nitromethylene neonicotinoid insecticides used in China. IPP was the promising replacement for imidacloprid as a result of its higher activity against imidacloprid-resistant insects. Two pairs of enantiomers, RR/SS-IPP and SR/RS-IPP, were separated by preparative high-performance liquid chromatography and employed in an aqueous system to investigate their biodegradation process. In this study, the strains G1 13/G1-14 and G2-19 with effective IPP degrading capability were isolated from agricultural soils. G1-14 was mutated from G1-13 by ultraviolet light exposure. Sequence alignment of 16S rRNA proved that these three strains belonged to the genus of Sphingobacterium. The degradation rate of RR/SS-IPP by Sphingobacterium sp. G1-13 and G1-14 reached 13 and 30% within 6 and 4 days, respectively. The degradation rate of SR/RS-IPP by Sphingobacterium sp. G2-19 could reach 35% within 5 days. Degradation intermediates (I1-I6) of enantiomers were detected, and two possible biodegradation pathways were proposed on the basis of the identification of metabolites. PMID- 27617493 TI - How Does Definition of Minimum Break Length Affect Objective Measures of Sitting Outcomes Among Office Workers? AB - BACKGROUND: Harmful health effects associated with sedentary behavior may be attenuated by breaking up long periods of sitting by standing or walking. However, studies assess interruptions in sitting time differently, making comparisons between studies difficult. It has not previously been described how the definition of minimum break duration affects sitting outcomes. Therefore, the aim was to address how definitions of break length affect total sitting time, number of sit-to-stand transitions, prolonged sitting periods and time accumulated in prolonged sitting periods among office workers. METHODS: Data were collected from 317 office workers. Thigh position was assessed with an ActiGraph GT3X+ fixed on the right thigh. Data were exported with varying bout length of breaks. Afterward, sitting outcomes were calculated for the respective break lengths. RESULTS: Absolute numbers of sit-to-stand transitions decreased, and number of prolonged sitting periods and total time accumulated in prolonged sitting periods increased, with increasing minimum break length. Total sitting time was not influenced by varying break length. CONCLUSIONS: The definition of minimum break length influenced the sitting outcomes with the exception of total sitting time. A standard definition of break length is needed for comparison and interpretation of studies in the evolving research field of sedentary behavior. PMID- 27617494 TI - Thwarting PTEN Expression by siRNA Augments HL-60 Cell Differentiation to Neutrophil-Like Cells by DMSO and ATRA. AB - Abnormal cell differentiation, in particular suppression of terminal cell differentiation, exists in all tumors. Therapeutic interventions to restore terminal differentiation ("differentiation therapy") are a very attractive way to treat cancer, especially leukemia. A variety of chemicals stimulates differentiation of leukemic cells, such as dimethyl sulfoxide (DMSO) and all trans retinoic acid (ATRA). Tumor suppressor genes have a vital role in the gateway to terminal cell differentiation. In this study, we inhibited PTEN tumor suppressor gene expression by siRNA to investigate the effect of potentiating cell survival and inhibiting apoptosis on HL-60 cell differentiation by DMSO and ATRA. Our results show that PTEN siRNA increases HL-60 cell differentiation in the presence of DMSO and ATRA. At the same time, the presence of siRNA hampers accumulation of apoptotic cells during incubation. Our study suggests that manipulation of PTEN could hold promise for enhancing efficacy of differentiation therapy of acute myelogenous leukemia. PMID- 27617495 TI - Formation of triploid plants via possible polyspermy. AB - Polyploidization is a common phenomenon in angiosperms, and polyploidy has played a major role in the long-term diversification and evolutionary success of plants. Triploid plants are considered as the intermediate stage in the formation of stable autotetraploid plants, and this pathway of tetraploid formation is known as the triploid bridge. As for the mechanism of triploid formation among diploid populations, fusion of an unreduced gamete with a reduced gamete is generally accepted. In addition, the possibility of polyspermy has been proposed for maize, wheat and some orchids, although it has been regarded as an uncommon mechanism of polyploid formation. One of the reasons why polyspermy is regarded as uncommon is because it is difficult to reproduce the polyspermy situation in zygotes and to analyze the developmental profiles of polyspermic zygotes. In the study, we produced polyspermic rice zygotes by electric fusion of an egg cell with two sperm cells and monitored their developmental profiles. The two sperm nuclei and the egg nucleus fused into a zygotic nucleus in the polyspermic zygote, and the triploid zygote divided into a two-celled embryo via mitotic division with a typical bipolar microtubule spindle. The two-celled proembryos developed and regenerated into triploid plants. These results suggest that polyspermic plant zygotes have the potential to form triploid embryos, and that polyspermy in angiosperms might be a pathway for the formation of triploid plants. PMID- 27617496 TI - Dysregulated Erythropoietin, Hepcidin, and Bone Marrow Iron Metabolism Contribute to Interferon-Induced Anemia in Hepatitis C. AB - Anemia is a complication of interferon-containing hepatitis C treatments. We characterized effects of interferon-based therapy on hepcidin and erythropoietin (EPO) production, iron metabolism, hemolysis, and hematopoiesis. Standard hemopoiesis [reticulocyte hemoglobin (Hb), reticulocyte production index (RPI), free Hb, and haptoglobin], iron biochemistry, hepcidin, and EPO levels were measured in 10 subjects over 12 weeks. There was a rapid decline in Hb during treatment, from a mean pretreatment (t = 0 weeks) Hb of 158.6 to 125.2 g/L at week 4 (P = 0.003) and 122.8 g/L at week 12 (P = 0.005). Paradoxically, the RPI (a measure of bone marrow responsiveness to EPO) decreased on initiation of hepatitis C virus treatment from 0.78% to 0.53% (P = 0.04). Despite worsening anemia, there was no significant increase in EPO levels. Hepcidin levels increased to >20 nM in 3 subjects from 5.8 to 27.5 nM (P = 0.009) compared with 9.6 to 12.3 nM (P = 0.5) for the remainder of subjects. Hepcidin levels peaked at week 1 before returning to baseline levels at week 4. Subjects who responded with a rise in serum hepcidin levels to >20 nM had a significantly greater drop in Hb (27.2 g/L, P = 0.008) and reticulocyte Hb (-1.4 g/L, P = 0.013) compared with the subjects who did not exhibit any change in hepcidin production. In conclusion, 30% of subjects treated with interferon exhibited significant transient increase in serum hepcidin levels, which was associated with more extreme anemia and decreased iron availability as evidenced by decreased reticulocyte Hb. In addition, there was a failure to upregulate EPO production in response to anemia and hemolysis ( https://clinicaltrials.gov trial NCT01726400). PMID- 27617497 TI - You Are What You Eat: The Impact of Nutrition on Alcohol and Drug Use. AB - BACKGROUND: Experimental research has shown that nutrition influences behavioral deviance. OBJECTIVES: The current project addresses the impact of nutrition on problem alcohol and drug use in a nationally representative sample of US adults. METHODS: The study relies on the daily dietary nutrition data and the substance use measures in the 2007-2008 National Health and Nutrition Examination Survey. RESULTS: The findings generally show that macronutrients increase the odds of substance use and micronutrients decrease the odds of substance use, especially among females. In addition, nutrient imbalance is a particularly strong predictor of substance use for both males and females. Depression partially accounts for the relationship between dietary nutrition consumption and substance use. CONCLUSIONS: Nutrition represents a promising extension of the biosocial perspective in substance use disorders. PMID- 27617498 TI - CYP2C9 and CYP2C19 Allele and Haplotype Distributions in Four Mestizo Populations from Western Mexico: An Interethnic Comparative Study. AB - AIMS: Polymorphisms in the CYP2C9 and CYP2C19 genes confer potential risk for specific adverse drug reactions and therapeutic effect failure. Their frequencies differ among ethnic groups. This study was aimed to describe the distribution of CYP2C9 and CYP2C19 alleles and haplotypes in four Mestizo populations from Western Mexico and their comparison with the reported data from other ethnic groups. METHODS: The CYP2C alleles (CYP2C9*2, CYP2C9*3, CYP2C19*2, and CYP2C19*3) were genotyped using polymerase chain reaction-restriction fragment length polymorphisms analyses using DNA samples from 477 healthy Mestizo individuals of Colima (n = 100), Jalisco (n = 147), Michoacan (n = 117), and Nayarit (n = 113). RESULTS: Frequencies ranged from 2.2-3.0% and 4.8-8.9% for CYP2C9*3 and CYP2C9*2 alleles, respectively, and 5.4-12.0% for CYP2C19*2, whereas the CYP2C19*3 allele was not found. Haplotype GACA, which harbors the loss-of-function allele CYP2C19*2, was the second most frequent (8.7%). Genetic heterogeneity between the Western Mexican populations studied here and the global population was evident (p < 0.05), except for most American populations and other Mexican Mestizo populations. CONCLUSION: Our findings increase the evidence for genetic variability at relevant pharmacogenetic loci and could be useful in association studies involving drugs that are substrates for CYP2C enzymes in the Western Mexican population. PMID- 27617500 TI - Kinesio taping or just taping in shoulder subacromial impingement syndrome? A randomized, double-blind, placebo-controlled trial. AB - OBJECTIVE: To verify effects of kinesio taping (KT) in shoulder subacromial impingement syndrome (SIS) when compared to sham taping applied in the same way with KT. PATIENTS AND METHODS: Patients were randomized as group 1 (n = 21) KT group and group 2 (n = 20) sham-taping group. Taping was applied every three days, three times during the study period. We assessed all the patients at baseline, at the end of the taping period (12th day), and at one-month post intervention. We assessed pain on the 100 mm visual analog scale (VAS). Shoulder range of motion (ROM), Constant Scores, and Nottingham Health Profile (NHP) scores were evaluated. RESULTS: Of the 41 participants, 13 were males (32%) and 28 were females (68%). The mean age was 45 +/- 15 years (range 20-65 years). We documented a significant decrease in VAS for nocturnal pain, and Constant Score in both groups. The KT group showed additional significant change in NHP pain and physical activity scores. CONCLUSION: KT and sham taping generated similar results regarding pain and Constant Scores. PMID- 27617501 TI - C3:CH50 ratio as a proposed composite marker for eculizumab monitoring in atypical hemolytic uremic syndrome: Preliminary results. AB - Treatment of atypical hemolytic uremic syndrome (aHUS) by the complement C5 inhibitor eculizumab (Soliris(r)) is highly effective but unfortunately, associated with an economic pressure on the health care systems even in high incomes countries. Despite spacing infusions having been proposed as the unique solution to minimize this economic impact, no reliable laboratory assays are available to tailor such therapy optimization. We aimed to propose and evaluate a complement composite marker for eculizumab efficacy monitoring in aHUS. We have retrospectively analyzed complement profiles data of eight aHUS patients under eculizumab from the International Registry of HUS/Thrombotic Thrombocytopenia Purpura, and calculated a novel marker "C3:CH50 ratio" by dividing C3 value by CH50 one for each sample during induction and maintenance periods. The results significance was compared to the currently used biomarkers for eculizumab tailoring. In contrast to the current biomarkers used for eculizumab efficacy monitoring like CH50 and soluble or deposit membrane attack complexes, "C3:CH50 ratio" seems to be the most interesting one since its value at pre-eculizumab dosage equaled 0.92 +/- 0.2 while the post-eculizumab one increased significantly to reach 24.54 +/- 10.7; P < 0.001. Furthermore, this ratio correlated negatively with platelets count (r = -0.722, P = 0.018) while no correlation was found within the thrombotic microangiopathy (TMA) biomarkers and complement blockade for the other parameters that change in pre and post-eculizumab therapy. As far as we know, this is the first study that suggests a post-eculizumab parameter correlating simultaneously with drug's activity (complement inhibition) and disease activity (platelets counts). Nonetheless, the limited number of patients enrolled in this study should be considered in larger studies to guide eculizumab optimization by indicating the time when subsequent withdrawal or infusion spacing is allowed or recommended. PMID- 27617502 TI - Effects of zinc and magnesium supplements on postpartum depression and anxiety: A randomized controlled clinical trial. AB - Postpartum anxiety and depression are prevalent disorders. The authors of this study aimed to determine the effects of zinc and magnesium supplements on depressive symptoms and anxiety in postpartum women referred to three governmental, educational hospitals in Tabriz, Iran during 2014-2015. In this triple-blind, randomized, controlled clinical trial, the participants were randomly assigned to the zinc sulfate, magnesium sulfate, and placebo groups (n = 33 per group). The intervention groups received a 27-mg zinc sulfate tablet or 320-mg magnesium sulfate tablet per day for 8 weeks, whereas the control group received a placebo tablet each day during the same period. The Edinburgh Postnatal Depression Scale and the Spielberger State-Trait Anxiety Inventory were completed before and 8 weeks after the intervention. Blood samples were drawn from each participant to determine serum levels of zinc and magnesium before intervention at 48 hours after delivery. Also, a 24-hour dietary questionnaire was used during the first and last 3 days of the intervention. Adjusting for baseline scores as well as zinc and magnesium serum levels, no significant difference was observed between groups 8 weeks after delivery in mean scores of depressive symptoms (p = .553), state anxiety (p = .995), and trait anxiety (p = .234). This study concluded magnesium and zinc did not reduce postpartum anxiety and depressive symptoms. PMID- 27617512 TI - Development of the Medical Maximizer-Minimizer Scale. AB - OBJECTIVE: Medical over- and underutilization are central problems that stand in the way of delivering optimal health care. As a result, one important question is how people decide to take action, versus not, when it comes to their health. The present article proposes and validates a new measure that captures the extent to which individuals are "medical maximizers" who are predisposed to seek health care even for minor problems, versus "medical minimizers" who prefer to avoid medical intervention unless it is necessary. METHOD: Studies 1-3 recruited participants using Amazon's Mechanical Turk. Study 1 conducted exploratory factor analysis (EFA) to identify items relevant to the proposed construct. In Study 2 confirmatory factor analysis (CFA) was conducted on the identified items, as well as tests of internal, discriminant, and convergent validity. Study 3 examined test-retest reliability of the scale. Study 4 validated the scale in a non Internet sample. RESULTS: EFA identified 10 items consistent with the proposed construct, and subsequent CFA showed that the 10 items were best understood with a bifactor model that assessed a single underlying construct consistent with medical maximizing-minimizing, with 3 of the 10 items cross-loading on another independent factor. The scale was distinct from hypochondriasis, distrust in medicine, health care access, and health status, and predicted self-reported health care utilization and a variety of treatment preferences. CONCLUSIONS: Individuals have general preferences to maximize versus minimize their use of health care, and these preferences are predictive of health care utilization and treatment preferences across a range of health care contexts. (PsycINFO Database Record PMID- 27617513 TI - Delivery of siRNA Using Lipid Nanoparticles Modified with Cell Penetrating Peptide. AB - Clinical development of siRNA has been hindered by the lack of an effective delivery system. Here, we report the construction of a novel siRNA delivery system, sTOLP, which is based on cell penetrating peptide oleoyl-octaarginine (OA R8) modified multifunctional lipid nanoparticles. sTOLP nanoparticles are composed of a protamine complexed siRNA core, OA-R8, cationic and PEGylated lipids, and transferrin as a targeting ligand. sTOLP formulation was optimized and characterized in vitro and showed excellent gene silencing activity. In vivo, siRNA encapsulated in sTOLP exhibited potent tumor inhibition (61.7%) and was preferentially taken up by hepatocytes and tumor cells in HepG2-bearing nude mice without inducing immunogenicity or hepatic or renal toxicity. Furthermore, sTOLP loaded siRNA had stability in circulation greater than that of free siRNA. These data demonstrated potential utility of sTOLP-mediated siRNA delivery in cancer therapy. PMID- 27617514 TI - Binary Protein Crystals for the Assembly of Inorganic Nanoparticle Superlattices. AB - Biomolecules can act as functional templates for the organization of inorganic particles. Here we use two protein containers, engineered with opposite surface charge, as building blocks for the construction of a new type of biohybrid material. Binary structures with crystalline order were obtained, adopting a tetragonal lattice. Moreover, the cavity of the engineered protein containers can be filled with inorganic nanoparticles. The controlled assembly of these protein nanoparticle composites yields highly ordered binary nanoparticle superlattices as free-standing crystals, with up to a few hundred micrometers in size. Because the structure and lattice parameters of the protein-nanoparticle crystals are independent of their nanoparticle cargo, the binary protein material may serve as a generally applicable matrix for the assembly of a variety of nanoparticles types. PMID- 27617515 TI - Hormones and clocks: do they disrupt the locks? Fluctuating estrogen levels during menopausal transition may influence clock genes and trigger chronic telogen effluvium. AB - Chronic telogen effluvium describes the clinical condition noted mostly in middle aged women of increased, diffuse scalp hair shedding that is prolonged and often presents with a fluctuating course that may continue for years but does not lead to visible hair thinning. Despite its description almost 20 years ago, the underlying pathologic cause of CTE is yet to be identified. However the culmination of research in the field of hair biology and the burgeoning field of chronobiology may lead to exciting breakthroughs in our understanding of CTE. In this paper the current literature on CTE is reviewed and a hypothesis is put forth that CTE may be triggered by hormonal fluctuations and alterations in circadian control genes. PMID- 27617516 TI - Tumor stage mycosis fungoides: a single-center study on clinicopathologic features, treatments, and patient outcome. AB - BACKGROUND: Tumor stage mycosis fungoides (MF) is a subtype of cutaneous T-cell lymphoma (CTCL). Tumor stage MF is rarely curable. Treatment is aimed towards controlling the disease and minimizing side effects from therapy. OBJECTIVE: To characterize clinicopathologic features of tumor stage MF and the impact of clinical characteristics and treatment modalities on patient outcome. METHODS: A retrospective chart review was conducted on 39 patients with tumor stage MF followed at Vanderbilt University between July 1995 and July 2010. RESULTS: The median age of diagnosis was 61 years (IQR: 54-70). Sixty-nine percent of the patients were male (27/39). The median follow-up time was 13.6 months (IQR: 5.5 35.9). Among the patients younger than 60 years at the time of initial diagnosis (n = 19), median overall survival (OS) was 7.0 years (95% CI: 2.1-17.9), compared with 3.3 years (95% CI: 2.4-9.3) in patients who were 60 years or older at initial diagnosis. Ten patients with T1/T2 stage at diagnosis had median OS of 5.0 years (95% CI 3.2-7.0). Twenty-eight patients with T3 stage at diagnosis had median OS of 5.8 years (95% CI 2.4-14.2). Median OS for patients with large cell transformation (LCT) and without LCT was 3.3 and 7.7 years, respectively. LIMITATIONS: This is a retrospective study with the bias of a tertiary-care referral center. CONCLUSION: Although LCT and older age at diagnosis were not statistically significant negative prognostic indicators of OS, there was a trend towards statistical significance for LCT. Clinical stage at diagnosis may not affect OS in patients who develop tumor stage MF. PMID- 27617517 TI - Goodness, gracious, great balls of fire: A case of transient lingual papillitis following consumption of an Atomic Fireball. AB - Transient lingual papillitis is a benign condition characterized by the inflammation of one or more fungiform papillae on the dorsolateral tongue. Although it is a common condition that affects more than half of the population, few cases have been reported in the dermatological literature. Therefore, it is a condition uncommonly recognized by dermatologists though it has a distinct clinical presentation that may be easily diagnosed by clinicians familiar with the entity. We report an interesting case of transient lingual papillitis in a 27 year-old healthy woman following the consumption of the hard candy, Atomic Fireball. We describe treatment and resolution of the condition, and its recurrence following re-exposure to the identified culprit. This report further reviews the literature to illustrate the clinical manifestations, etiology, differential diagnosis, course, and treatment of this condition. PMID- 27617518 TI - Lhermitte-Duclos Disease in association with Cowden Syndrome. AB - Cowden syndrome (CS) is a rare genetic disorder with autosomal dominant inheritance, linked to germline mutations in the PTEN tumor suppressor gene on chromosome 10. Cowden syndrome often co-exists with Lhermitte-Duclos disease (LDD), with LDD included as a major criterion in CD diagnosis. This case involves a woman presenting with many of the classic diagnostic criterions and associations of CD, as well as with several comorbidities and unique objective findings. PMID- 27617519 TI - Intravascular papillary endothelial hyperplasia of the vulva: report of a patient with Masson tumor of the vulva and literature review. AB - BACKGROUND: Intravascular papillary endothelial hyperplasia -- also known as Masson tumor -- is a rare, benign vascular condition that manifests on the skin as a firm, blue-black colored nodule or papule. Lesions range in size from 0.25 to 5 centimeters in diameter and may be tender or painless. In some individuals, nodules appear red colored, mimicking hemangioma or pyogenic granuloma. Histologically, intravascular papillary endothelial hyperplasia is characterized by the presence of an organizing thrombus in the vascular lumen with accompanying hyperplastic endothelial cell proliferation. Common sites of presentation include the head, neck, and extremities. However, albeit rarely, lesions may also appear in the genital region. PURPOSE: We describe the clinical and pathologic findings of a woman who developed intravascular papillary endothelial hyperplasia of the vulva. We also review the characteristics of other patients with intravascular papillary endothelial hyperplasia of the vulva and summarize the differential diagnosis and treatment options for this condition. MATERIALS AND METHODS: The features of a woman with intravascular papillary endothelial hyperplasia of the vulva are presented. Using PubMed, the following terms were searched and relevant citations assessed: intravascular papillary endothelial hyperplasia, IPEH, labia majora, Masson hemangioma, Masson pseudoangiosarcoma, Masson tumor, and vulva. In addition, the literature on intravascular papillary endothelial hyperplasia is reviewed. RESULTS: A 32-year-old woman presented with a 3 x 2 millimeter painless, black colored submucosal papule on her left labia majora. The lesion was removed by excisional biopsy. Microscopic examination revealed a re canalizing thrombus and a proliferation of erythrocytes within a dilated vascular structure. Based on correlation of the clinical presentation and histopathologic findings, a diagnosis of intravascular papillary endothelial hyperplasia was established. The patient applied mupirocin 2% ointment to the biopsy site, which subsequently healed without complication or recurrence. CONCLUSION: Intravascular papillary endothelial hyperplasia -- also known as Masson tumor -- is a rare, benign vascular eruption. Cutaneous lesions typically present as red colored or blue-black colored nodules ranging in size from 0.25 to 5 centimeters in diameter. The most common sites of presentation include the head, neck, and extremities. However, albeit rarely, lesions may also appear in the genital region. The histologic hallmark of intravascular papillary endothelial hyperplasia is an organizing thrombus in the vascular lumen with associated hyperplastic endothelial cell proliferation. Lesions often appears similar to other neoplastic and non-neoplastic cutaneous tumors, including hemangiomas, pyogenic granulomas, and cutaneous angiosarcomas. Therefore, pathologic examination is required to confirm the suspected diagnosis and exclude malignancy. The condition can usually be treated with simple local excision. PMID- 27617520 TI - Plasmablastic lymphoma: an atypical cutaneous presentation of a rare entity. AB - Plasmablastic lymphoma is a very rare B-cell lymphoma typically associated with immunosuppression: It occurs primarily in the oral cavity, although some cases were reported in other organs and tissues.To date, only 10 cases of primary cutaneous plasmablastic lymphoma have been described. Clinically, primary cutaneous plasmablastic lymphoma presents as non-specific cutaneous lesions (purple nodules, erythematous infiltrated plaques). In previously described cases, as in this case, histology and immunohistochemistry are required to make the diagnosis. Owing to the rarity of this entity, there is no established therapy, which makes its management an individualized, patient-based decision. PMID- 27617521 TI - Successful treatment of pityriasis lichenoides chronica with narrow-band ultraviolet B therapy in a patient with Keratitis-Ichthyosis-Deafness syndrome: a case report. AB - Keratitis-ichthyosis-deafness (KID) syndrome is a rare genodermatosis causing ichthyosis-like skin lesions, keratitis, and deafness. Herein, we report a patient with this rare syndrome in association with pityriasis lichenoides chronica, which was succesfully treated with narrow-band ultraviolet B phototherapy despite our concerns regarding the increased risk of squamous cell carcinoma, hyperpyrexia, and keratitis. PMID- 27617522 TI - Pigmented hidrocystoma of nasal epithelium (PHONE): report of a man with a pigmented hidrocystoma of his nose and literature review. AB - BACKGROUND: Hidrocystomas are benign tumors of apocrine or eccrine epithelium. They most commonly occur on the head and neck, especially periorbitally. Albeit rare, these adnexal tumors may present as pigmented lesions. PURPOSE: To describe a patient with a pigmented eccrine hidrocystoma of his nose and to review the features of other individuals with pigmented hidrocystoma of the nasal epithelium. MATERIAL AND METHODS: PubMed was used to search the follow terms: hidrocystoma and pigmented. All papers were reviewed and relevant manuscripts, along with their reference citations were evaluated. RESULTS: A 52-year-old man who presented with a pigmented eccrine hidrocystoma on his nasal bridge was described. The features of three previously described patients with pigmented hidrocystoma of the nose were evaluated. The tumors presented as single or multiple, less than 2mm, blue papules. Our patient's tumor would intermittently bleed, which prompted consideration of a possible basal cell carcinoma. Biopsy established the diagnosis showing a cystic lesion lined by eccrine epithelium with pigmented secretion within the cyst's lumen. The cyst content stained positive with Fontana-Masson stain. Our patient's excisional biopsy resulted in excellent cosmetic appearance and complete removal of the benign adnexal tumor. CONCLUSION: Pigmented hidrocystomas may be mistaken for other skin lesions, such as a pigmented basal cell carcinoma and melanoma. A biopsy readily establishes the diagnosis. We respectfully suggest that a hidrocystoma located on the nose that is pigmented be referred to as a PHONE: pigmented hidrocystoma of the nasal epithelium. PMID- 27617523 TI - Milia-like idiopathic calcinosis cutis in a child with Down syndrome. AB - Idiopathic calcinosis cutis refers to progressive deposition of crystals of calcium phosphate in the skin and other areas of the body, in the absence of any inciting factor. Idiopathic calcinosis cutis may sometimes take the form of small, milia-like lesions. Most commonly, such milia like lesions are seen in the setting of Down syndrome. Herein, we report a 5-year-old girl with multiple asymptomatic discrete milia-like firm papules distributed over the face and extremities. A diagnosis of milia-like idiopathic calcinosis cutis associated with Down Syndrome was provisionally made and was confirmed by histopathology and karyotyping. PMID- 27617524 TI - Cutaneous Richter Syndrome mimicking a lower limb cellulitis infection - a case report and review of the literature. AB - Richter syndrome (RS) is characterized by the development of a high-grade lymphoma in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Herein, we present the case of an 85-year-old woman with a 3-year history of stable asymptomatic CLL that developed a cutaneous RS. The patient presented with painless inflammation in the left leg and foot that was initially diagnosed as a cellulitis infection. She was treated accordingly with ceftriaxone and clindamycin. However, after completing the antibiotic regimen, not only did the inflammation persist, but also superimposed painless nodules gradually appeared on the left leg and foot over the course of four months. The histopathological examination of the nodules revealed a large B-cell cutaneous lymphoma. The patient underwent chemotherapy with CVP, followed by R-CHOP, resulting in a reduction of size of the nodules and remission of the inflammation. The patient died five months after the diagnosis owing to a bacterial pneumonia. We identified in previous reports a total of fifteen cases of cutaneous RS. Most cases presented with rapidly growing tumors or multiple erythematous nodules, similar to our case. This case of a cutaneous RS mimicking a cellulitis infection underlines the importance of a low threshold for performing biopsies of suspicious skin lesions in patients with CLL/SLL. PMID- 27617526 TI - Penicillamine-associated cutis laxa and milia en plaque - case report and review of cutaneous changes associated with penicillamine. AB - Penicillamine-induced skin changes are rare and include: hypersensitivity reactions, autoimmune reactions, and cutaneous elastoses. We report a case of a 73-year-old man with cystinuria taking penicillamine for over 50 years who presented with penicillamine-induced cutis laxa and milia en plaque. A brief review of penicillamine induced skin changes, specifically cutis laxa and milia en plaque, is presented. PMID- 27617525 TI - Criptococosis cutanea primaria en paciente inmunocompetente. AB - La criptococosis cutanea es una micosis propia de pacientes inmunodeprimidos, sobre todo aquellos con infeccion por el virusde la inmunodeficiencia humana (VIH). Sin embargo, existen casos infrecuentes de criptococosis cutanea en pacientes inmunocompetentes, que suelen simular otras dermatosis, lo que retrasa su diagnostico y tratamiento. Presentamos el caso de un varon pluripatologico de 79 anos, con ulceras dolorosas en dorso de mano derecha que no respondian a tratamientos topicos. A traves del estudio histopatologico y micologico se alcanzo el diagnostico de criptococosis cutanea primaria, lograndose la remision de las lesiones tras 6 meses de tratamiento con fluconazol. PMID- 27617527 TI - Infantile myofibroma: a firm, round plaque in an infant. AB - Infantile myofibroma is a rare fibromatous tumor that is variable in presentation and is frequently mistaken for hemangioma or rhabdomyosarcoma. We describe a 14 month-old boy who presented with multiple, enlarging, firm lesions on the shoulder. Biopsy revealed a proliferation of small spindle cells with myxoid and hyalinized stroma infiltrating into the superficial adipose tissue. We provide a brief review of the clinical presentation, histopathologic features, management, and recent advances in our understanding of this rare condition. PMID- 27617528 TI - Micosis fungoide e inhibidores del TNFalpha: ?riesgo o beneficio? AB - The growing use of anti-TNF drugs during the last years has reopened the discussion about the possible increased risk of developing non-Hodgkin lymphoma in patients with such type of treatments. We present our clinical experience and critical opinion about the current situation of such issue regarding cutaneous T cell lymphomas.El creciente uso de farmacos anti-TNF durante los ultimos anos ha reabierto el debate sobre el posible aumento de riesgo de linfomas no Hodgkin en los pacientes con este tipo de tratamientos. Presentamos nuestra experiencia clinica y opinion critica sobre la situacion actual de este tema en relacion a los linfomas cutaneos de celulas T. PMID- 27617529 TI - Hypotrichosis with juvenile macular dystrophy: Portuguese case. AB - Hypotrichosis with juvenile macular dystrophy is a rare congenital disease mainly found in the Druze population of Northern Israel. This disorder is caused by the CDH3 mutation encoding P-cadherin, which is expressed in retinal pigment epithelium and hair follicles. An 11-year-old girl who was born to related Portuguese parents, had hypotrichosis since birth and macular dystrophy diagnosed at age 5. Fundus examination and fluorescein angiography revealed located macular pigmentary abnormalities. No molecular analysis was done. A fundus examination should be considered mandatory in the assessment of congenital hypotrichosis. PMID- 27617530 TI - Increasing adherence to topical therapy in psoriasis through use of solution medication. AB - Patient outcomes and clinical improvement are closely related to topical medication adherence, and is especially important in chronic dermatological diseases such as psoriasis. About one-fifth of patients undergoing topical treatment were dissatisfied with its convenience for various reasons. Providers can help increase adherence through selecting the correct medication vehicle, involving family members or friends in the patient's mediation application, and explaining likely side effects to the patient prior to use of the medication. Increased inherence will lead to better psoriasis disease control. PMID- 27617531 TI - Angioqueratomas de fordyce multiplos de vulva associados a cirrose hepatica. AB - Fordyce angiokeratoma is a benign skin neoplasm, characterized by erythematous violet keratotic papules with mamillated surface, which follows a chronic and minimally symptomatic course. However, symptoms can be related such as itching, burning, bleeding, dyspareunia; aesthetic and social concerns may prompt request for treatment. The condition mainly affects men and usually occurs in the scrotum, but rarely may occur in women. A 30-year-old woman with liver cirrhosis and portal hypertension is described. Over a period of two years she developed multiple angiokeratomas of the vulva, complicated by frequent bleeding. Histopathologic analysis of the lesion confirmed the diagnosis of angiokeratoma and all lesions were surgically removed. The results of the treatment were very satisfactory, with no relapses or complications.Angioqueratoma de Fordyce e uma dermatose incomum que compoe o grupo das neoplasias cutaneas benignas, caracterizando-se pelo aparecimento de lesoes papuloceratosicas, eritemato violaceas de superficie mamilonada, que apresentam curso cronico e oligossintomatico. No entanto, outros sintomas podem estar associados, como prurido, ardencia, sangramento e dispareunia, alem de problemas esteticos e de ordem social. Afeta principalmente homens, acometendo a regiao escrotal, sendo raro seu surgimento em mulheres. Relata-se caso de uma paciente com 30 anos de idade, portadora de cirrose hepatica e hipertensao portal evoluindo ha 2 anos com multiplos angioqueratomas na vulva de sangramento frequente. A analise histopatologica confirmou o diagnostico de angioqueratoma e a paciente foi submetida a exerese cirurgica das lesoes. Os resultados terapeuticos foram satisfatorios, sem recidivas ou complicacoes. PMID- 27617532 TI - Visual morphometry and three non-invasive markers in the evaluation of liver fibrosis in chronic liver disease. AB - OBJECTIVE: Liver fibrosis is traditionally graded into categorical stages with cirrhosis as the highest stage. However, cirrhosis stage may vary between individuals widely in terms of the amount of fibrosis which is not assessed by traditional staging systems. We aimed to utilise visual morphometry to quantify the amount of fibrosis in liver biopsy and compare how non-invasive methods of quantifying liver fibrosis correlated with histological measures. MATERIALS AND METHODS: Liver biopsy specimens from 115 consecutive chronic liver disease patients were assessed by a single pathologist for fibrosis stage by the Clinical Research Network and METAVIR systems as well as percentage fibrosis by visual morphometry. Liver T1 relaxation times, liver stiffness measurement (LSM) by transient elastography and enhanced liver fibrosis (ELF) score were compared between fibrosis stages. In addition, these parameters were correlated with pathologist's visual estimate of percentage fibrosis and their predictive ability for advanced fibrosis and cirrhosis assessed by area under receiver operating curve (AUROC). RESULTS: All four parameters increased sequentially from fibrosis stage F0 to F4 (p<.001 for each). AUROCs for advanced fibrosis and cirrhosis were 0.931 and 1.000 respectively for pathologist's estimate of fibrosis, 0.707 and 0.926 for ELF score, 0.763 and 0.972 for T1 and 0.881 and 0.989 for LSM. LSM, ELF score and T1 correlated significantly with pathologist's estimate of percentage fibrosis. CONCLUSION: Non-invasive markers of fibrosis LSM, ELF and T1 relaxation time provide continuous surrogates for categorical histopathological staging of fibrosis which can be useful as markers of progression and regression of fibrosis on follow-up. PMID- 27617533 TI - Diversification of school psychology: Developing an evidence base from current research and practice. AB - Why is there a need to increase the racial/ethnic diversity of faculty in school psychology? Chiefly, school psychologists serve the most racially/ethnically diverse population: children in US schools. Therefore, developing a knowledge base that is inclusive of this wide range of perspective as well as growing a workforce that is reflective of this diversity is essential to effective service delivery. To achieve this goal, school psychology trainers must develop evidence based, purposeful efforts to recruit and retain racial/ethnic minority students in doctoral programs. For these reasons, we called for a special issue on diversifying the field of school psychology. The purpose of this special issue is to advance the evidence-base in school psychology on how to increase diverse scholars and leaders in the profession. Moreover, the goal is to also evaluate the status of the profession in effectively recruiting and retaining racial/ethnic minority graduate students, mentoring racial/ethnic minority students to pursue careers in academia, and promoting faculty development and retention of racially and ethnically diverse faculty. Thus, the articles in this special issue will address critical areas where trainers can improve recruitment and retention strategies that will increase the racial/ethnic diversity of school psychology faculty, leaders, and practitioners. (PsycINFO Database Record PMID- 27617534 TI - Recruitment and retention of Native American graduate students in school psychology. AB - There is a clear underrepresentation of Native Americans in the field of school psychology. There are a number of factors that have led to this underrepresentation, including cultural and historical variables, barriers to accessing higher educational opportunities, and lack of financial support. Given the importance of having diverse perspectives in the field, as well as the need for mental health services and academic supports for Native American children and their families, school psychology trainers should consider actively recruiting and retaining Native American graduate students to doctoral and specialist programs. This article provides specific research-based recommendations for recruiting Native American students and strategies for supporting their success and matriculation in the program. (PsycINFO Database Record PMID- 27617535 TI - INTRAPAPILLARY PROLIFERATION IN OPTIC DISK PITS: Clinical Findings and Time Related Changes. AB - PURPOSE: To investigate the structural changes of intrapapillary proliferations associated with optic disk pits (ODPs) and optic disk pit maculopathy (ODP-M) using enhanced depth-spectral domain-optical coherence tomography (SD-EDI-OCT) and megahertz optical coherence tomography (MHz-OCT). METHODS: Sixteen eyes of patients with ODPs were studied. Papillary and peripapillary areas were repeatedly examined with SD-EDI-OCT over time. To evaluate swept-source OCT, some of the patients additionally received MHz-OCT-imaging. RESULTS: MHz-OCT or SD-EDI images showed the entire form of the pits from opening to bottom in 13 of the 16 cases. The shape of ODPs varied considerably. In patients with unilateral ODP, deep intrapapillary depressions in the optic disk of the contralateral partner eye were a prevalent finding. Intrapapillary proliferations were observed in all ODP-cases during follow-up. The aspect of intrapapillary and prepapillary tissue, septae, and cavities changed over time. This effect was especially pronounced inside the ODP while the eye experienced simultaneous ODP-M. CONCLUSION: All examined eyes with ODP showed signs of intrapapillary and prepapillary tissue, which developed over time. SD-EDI-OCT and MHz-OCT are able to detect characteristic ODP-related findings and are a useful means to monitor time related changes within intrapapillary and prepapillary tissue related to ODP and ODP-M. PMID- 27617536 TI - THE EFFECT OF INTERNAL LIMITING MEMBRANE PEELING ON IDIOPATHIC EPIRETINAL MEMBRANE SURGERY, WITH A REVIEW OF THE LITERATURE. AB - PURPOSE: To examine the effect of internal limiting membrane (ILM) removal on epiretinal membrane (ERM) surgery by comparing best-corrected visual acuity (BCVA), optical coherence tomography central macular thickness (CMT) changes, ERM recurrence, and need for repeat surgery. METHODS: Retrospective study of 251 consecutive patients (251 eyes) who underwent pars plana vitrectomy for idiopathic ERM by a single surgeon with over 1 year of follow-up data. Data were collected preoperatively and postoperatively at 3 months, 1 year, 2 years, and at the last visit. The ILM was not specifically removed in the earlier group of patients and was removed after staining of the ILM in the later group. RESULTS: One hundred and forty eyes (55.8%) did not have an ILM peel (non-ILM group), and 111 eyes (44.2%) did have an ILM peel (ILM group). There were no significant differences between groups in age, gender, preoperative BCVA, preoperative intraocular pressure, preoperative CMT on optical coherence tomography, and cataract status. Total follow-up time for the ILM group was 32.1 months and 45.4 months for the non-ILM group (P = 0.002). Both groups had improvement in BCVA. The ILM group improved by 12 Early Treatment Diabetic Retinopathy Study letters and the non-ILM group improved by 10.5 Early Treatment Diabetic Retinopathy Study letters. There was no significant difference in the final BCVA (P = 0.18) or total change of BCVA (P = 0.48). Cataract status preoperatively did not affect the total change of BCVA, but being phakic at the most recent visit was associated with a slight loss of visual acuity. Both groups had improvement in optical coherence tomography appearance, for the CMT in the ILM group decreased by 83 MUm and the CMT in the non-ILM group decreased by 110 MUm. There was no significant difference in the final CMT (P = 0.07); however, the non-ILM group tended to have a lower final CMT. Some degree of ERM recurrence was detected by slit-lamp biomicroscopy in 2 eyes (1.8%) of the ILM group and in 32 eyes (22.9%) of the non-ILM group (P <= 0.0001). None of the eyes with ILM removal required repeat vitrectomy, whereas 17 eyes (12.1%) of the non-ILM group did require vitrectomy, showing that ILM removal had a significant effect on the need for repeat vitrectomy (P < 0.0001) between non-ILM versus ILM peel groups. CONCLUSION: The rate of recurrent ERM and need for repeat ERM surgery is lower in eyes where the ILM is removed with the ERM, whereas BCVA and CMT were similar with or without ILM removal. Complete ILM removal around the macula should be considered for the treatment of eyes with idiopathic ERMs to reduce the incidence of ERM recurrences. PMID- 27617537 TI - SERUM LEVELS OF VASCULAR ENDOTHELIAL GROWTH FACTOR BEFORE AND AFTER INTRAVITREAL INJECTION OF RANIBIZUMAB OR CONBERCEPT FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION. AB - OBJECTIVE: To investigate the serum levels of vascular endothelial growth factor (VEGF) before and after intravitreal injection of conbercept or ranibizumab for neovascular age-related macular degeneration and polypoidal choroidal vasculopathy patients. METHODS: This study is a prospective, interventional case series and involved 28 patients, 18 treated with 0.5 mg of conbercept and 10 treated with 0.5 mg of ranibizumab. Serum concentrations of VEGF were determined by enzyme-linked immunosorbent assay before the injection and at 1 day, 1 week, and 1 month after anti-VEGF treatments. RESULTS: The baseline serum VEGF level of the ranibizumab group was 367.11 +/- 311.87 pg/mL, whereas that of the conbercept group was 315.06 +/- 170.88 pg/mL (P = 0.653). In the conbercept group, VEGF level significantly decreased to 36.32 +/- 72.11 pg/mL at 1 day (P = 0.03) and returned to 136.55 +/- 144.62 pg/mL at 1 week (P = 0.03). At 1 month, the concentration increased to 334.48 +/- 197.41 pg/mL and showed no significant difference compared with the baseline. In the ranibizumab group, the serum VEGF levels were 292.42 +/- 239.80 pg/mL, 282.60 +/- 201.36 pg/mL, and 308.83 +/- 266.89 pg/mL at 1 day, 1 week, and 1 month after intravitreal injection, respectively. There was no significant difference in the ranibizumab group at each detection time point (P = 0.45). CONCLUSION: Conbercept significantly decreased serum VEGF level 1 day and 1 week after injection, but this effect was not sustained for 1 month. In contrast, ranibizumab had no significant effect on serum VEGF concentration changes. The reduction in serum VEGF by conbercept may affect its systemic safety profile. PMID- 27617538 TI - EPIDEMIC OF PATHOLOGIC MYOPIA: What Can Laboratory Studies and Epidemiology Tell Us? AB - PURPOSE: To systematically review epidemiologic and laboratory studies on the etiology of high myopia and its links to pathologic myopia. METHODS: Regular Medline searches have been performed for the past 20 years, using "myopia" as the basic search term. The abstracts of all articles have been scrutinized for relevance, and where necessary, translations of articles in languages other than English were obtained. RESULTS: Systematic review shows that there is an epidemic of myopia and high myopia in young adults in East and Southeast Asia, with similar but smaller trends in other parts of the world. This suggests an impending epidemic of pathologic myopia. High myopia in young adults in East and Southeast Asia is now predominantly associated with environmental factors, rather than genetic background. Recent clinical trials show that the onset of myopia can be reduced by increasing the time children spend outdoors, and methods to slow the progression of myopia are now available. CONCLUSION: High myopia is now largely associated with environmental factors that have caused the epidemic of myopia in East and Southeast Asia. An important clinical question is whether the pathologic consequences of acquired high myopia are similar to those associated with classic genetic high myopia. Increased time outdoors can be used to slow the onset of myopia, whereas methods for slowing progression are now available clinically. These approaches should enable the current epidemics of myopia and high myopia to be turned around, preventing an explosion of pathologic myopia. PMID- 27617539 TI - CLINICAL RELEVANCE OF AQUEOUS VASCULAR ENDOTHELIAL GROWTH FACTOR LEVELS IN POLYPOIDAL CHOROIDAL VASCULOPATHY. AB - PURPOSE: To investigate vascular endothelial growth factor (VEGF) level according to the clinical and imaging features, and to explore its relationship with the responsiveness to anti-VEGF treatment in eyes with polypoidal choroidal vasculopathy. METHODS: Aqueous samples were collected from 62 eyes of 62 patients with treatment-naive polypoidal choroidal vasculopathy. Vascular endothelial growth factor levels were measured using enzyme-linked immunosorbent assay. Baseline best-corrected visual acuity, central macular thickness, subfoveal choroidal thickness, greatest linear dimension of the lesion, and the presence of hemorrhage were included in the analysis. The effects of 3 monthly intravitreal ranibizumab injections on best-corrected visual acuity and central macular thickness were assessed. RESULTS: Baseline VEGF level was negatively correlated with subfoveal choroidal thickness (r = -0.33, P = 0.01). Other variables had no correlation with VEGF level. The mean change in central macular thickness after anti-VEGF treatment was -51 +/- 64 MUm, which is positively correlated with VEGF concentration (r = 0.30, P = 0.04) and negatively correlated with subfoveal choroidal thickness (r = -0.35, P = 0.02). CONCLUSION: Vascular endothelial growth factor level demonstrated a negative correlation with baseline subfoveal choroidal thickness and was associated with response to anti-VEGF treatment. These findings suggest that VEGF has a variable contribution to the pathogenesis of polypoidal choroidal vasculopathy depending on choroid thickness. PMID- 27617540 TI - Correspondence. PMID- 27617541 TI - LONG-TERM OUTCOMES AND INCIDENCE OF RECURRENCE OF NEOVASCULARIZATION IN TREATED EXUDATIVE AGE-RELATED MACULAR DEGENERATION. AB - PURPOSE: To assess the long-term visual outcome and incidence of recurrence of neovascular age-related macular degeneration (NAMD) treated with intravitreal anti-VEGF injections (IVAI). METHODS: One hundred and thirty-two consecutive eyes treated with IVAI for NAMD based on an as-needed regimen with a follow-up >=5 years (mean 7.55, range 5-9.67) were retrospectively reviewed. Main outcome measures included visual acuity, yearly number of IVAI, and occurrence of a long term remission, defined as no recurrence of NAMD for >=12 consecutive months. RESULTS: Mean baseline visual acuity was 20/100. Mean final visual acuity change was -3.41 letters. Mean overall IVAI number was 22.8 +/- 17.4 (range 2-71), decreasing from 4.6 during Year 1 to 2.21 during Year 8. A significant positive correlation was found between the number of IVAI during the first year of treatment and the overall number of IVAI during 5 years, 6 years, 7 years, or 8 years follow-up (r = 0.67-0.70, P <0.0001). Long-term remission occurred at least once in 83/132 eyes (63%) and was associated with a better visual outcome (-1.04 vs. -7.43 letters, P = 0.034). Incidence of yearly remission of NAMD increased from 28% during Year 2 to 59% during Year 8, fitting along a single straight line (+5.231%/year, R = 0.9511). CONCLUSION: The incidence of recurrence of treated NAMD decreases slowly but steadily during follow-up. The number of years of follow-up is the main factor to assess the proportion of treated eyes at remission at a given moment. Incidence of recurrence of neovascularization during year 1 and length of follow-up are significant factors when tailoring an optimal long-term follow-up regimen. PMID- 27617542 TI - OCULAR PHARMACOLOGY OF CHEMOTHERAPY FOR RETINOBLASTOMA. AB - PURPOSE: To review preclinical and clinical pharmacokinetic studies of the three most important chemotherapy drugs used for intraocular retinoblastoma and the contribution of the reported results to optimize treatment. METHODS: Systemic review of pharmacokinetic studies identified by a literature search at Pubmed using the keywords carboplatin, melphalan, topotecan, intravitreal, ophthalmic artery chemosurgery, pharmacokinetics, and retinoblastoma. RESULTS: A total of 21 studies were reviewed for assessing the preclinical and clinical pharmacokinetics of carboplatin, topotecan, and melphalan delivered by intravenous, periocular, ophthalmic artery, and intravitreal routes. Some preclinical studies were done before translation to the clinics. Others, despite encouraging preclinical data as reported for periocular topotecan did not correlate with clinical use. In addition, as was the case for melphalan after ophthalmic artery chemosurgery and despite nonfavorable preclinical information, some routes of drug delivery are clinically effective. Besides topotecan, complete knowledge of the pharmacokinetics of melphalan and carboplatin is still lacking. CONCLUSION: Pharmacokinetic knowledge of chemotherapy may aid to guide retinoblastoma treatment in favor of safety and efficacy. Nonetheless, results obtained in preclinical models should be translated with care to the clinics. PMID- 27617545 TI - Silicone Oil Removal From the Anterior Chamber. PMID- 27617546 TI - Reply. PMID- 27617547 TI - Reply. PMID- 27617548 TI - Reply. PMID- 27617549 TI - [Predictive score of success adapted to our environment to improve results of extracorporeal lithotripsy]. AB - OBJECTIVE: To present a predictive tool of success of ESWL adapted to our environment. METHODS: We performed a retrospective, descriptive and analytical study of patients with renal and upper ureteral stones whom underwent ESWL with DUET MAGNA lithotripter between January 2014 and March 2015. We included 114 patients in whom demographics and CT scan characteristics were studied. Multivariate analysis by logistic regression was performed to establish independent predictors of success in ESWL. A ROC curve was used to determine success cut-off values of ESWL in each significant variable. The score was established based on the numbers of variables under the cut-off value in each patient. In every one of these categories, percentage of stone free was determined. Finally, the area under the curve of our ESWL treatment success score was made. RESULTS: Of 114 patients studied, 58 (51%) were stone free. After multivariate study, independent predictors of success with ESWL were tomographic density of lithiasis (UH), body mass index (BMI) and stone diameter (mm). Ideal cut off points of treatment success in each one of the score parameters were: density of lithiasis 900 UH, BMI 27 and lithiasis diameter 11 mm. Percentage of stone free was 31.8% for score 0, 37.1% for score 1, 57.5% for score 2 and 88.3% for score 3. Area under the curve for the score was 0.723 (p<0.001). CONCLUSIONS: This score could represent a predictive tool in our environment to predict ESWL results. Utilization of this score could limit the use of this therapy only to patients with favorable profile (score2-3) improving in this way cost effectiveness of this procedure. PMID- 27617550 TI - [Treatment of pediatric lithiasis in the lithotripsy and endourology unit of "Hospital La Luz". Commented retrospective of our case series]. AB - OBJECTIVE: The aim of the present article is to summarize the results we obtained treating children with urolithiasis over the last 30 years and to perform an analysis on the basis of the these results and relevant details according to national and international experience. METHODS: Retrospective and descriptive statistical analysis of the 30 year experience in our clinics. The study was performed with a sample size of 178 children treated with urolithiasis that underwent 221 procedures. These procedures include ESWL, ureterorenoscopy (URS) and percutaneous nephrolithotomy (PCNL). CONCLUSIONS: We conclude in this study that ESWL in children was the most appropriate procedure for renal and proximal and middle-third ureteral lithiasis. Kidney stones measuring 2 to 3 cm can be treated without additional procedures or combined approaches. In contrast cystine stones caused the major problems for fragmentation. Moreover, the use of double J catheters increased the need for ESWL when catheter calcification occurred and endoscopic removal was impossible. The benefits of this method must be individually assessed both for the benefit of the temporary placement as well as for the expectation of permanence. We conclude that URS is the best choice for distal-third ureteral lithiasis and some cases of proximal and middle- third ureteral lithiasis. This enables for simultaneous treatments, ureteral dilatation and unexpected diagnoses. In particular, rigid ureteroscopy offers adjuvant options to ESWL with great therapeutic potential and easy handling. In consequence, to our good results and cost-benefit balance using ESWL and rigid URS (even combined), the use of flexible URS for renal lithiasis has been reduced. In general community units like ours, the combined PCNL has been indicated for particular complex cases, and open or laparoscopic surgery was not necessary in any case. PMID- 27617551 TI - [Diagnosis of urethral stenosis and follow-up after Urethroplasty]. AB - This article presents a review of the different tests used for the evaluation and follow-up of urethral strictures. Because there is no consensus on how to assess urethral pathology, we reviewed each of the next follow-up tests: questionnaires, uroflowmetry, ultrasound, urethroscopy, urethrogram, CT scan and MRI, outlining their benefits and limitations in the diagnosis and follow-up of urethral stricture. Urethrogram and urethroscopy are the most commonly used tests, as they are those that give us more information on the evaluation of stenosis and for surgery planning. Questionnaires and uroflowmetry play a key role in the follow up of these patients. Ultrasonography has high sensitivity and specificity for evaluating the spongiofibrosis, however it is not done routinely. The CT/MRI is recommended in the evaluation of pelvic trauma associated with fractures. PMID- 27617552 TI - Failure of Bacillus Calmette-Guerin therapy in non-muscle-invasive bladder cancer: Definition and treatment options. AB - Adjuvant intravesical bacillus Calmette- Guerin (BCG) therapy is the standard conservative adjuvant treatment and the most effective regimen for patients with high-risk non-muscle-invasive bladder cancer (NMIBC). The term "BCG failure" is generally used to refer to recurrence or progression following BCG therapy, as experienced by many patients. However, the term has been defined inconsistently, and several studies have indicated that patients with a particular pattern of BCG failure have a worse prognosis. There are many different treatment options for patients who experience BCG failure. OBJECTIVE: To summarize the different current definitions of BCG failure and the present treatment options available for patients with high-risk NMIBC who experience BCG failure. EVIDENCE SYNTHESIS: Overall, the failure rate in response to BCG is about 40-50%. Most guidelines recommend that patients failing BCG should be offered radical cystectomy (RC). The significant potential for progression specific to high-risk NMIBC leads some clinicians to argue that immediate RC should be considered the preferred first line treatment in high-risk patients, bearing in mind that it achieves a long term survival rate in excess of 90% with ongoing improvements in morbidity. While other salvage intravesical treatments have to be considered oncologically inferior to RC, several therapies are now available if the patient is unfit to undergo RC or if bladder preservation is the objective, and some agents have shown promise in the context of BCG failure. CONCLUSIONS: The definition, prediction, and treatment of BCG failure remain topics of debate. Patients with BCG failure need carefully selected, individualized therapy in experienced hands. Stratification of patients with BCG failure into groups can identify those with a better or worse prognosis. RC should be the selected option if a patient experiences BCG failure, but several promising intravesical salvage options are available for those cases in which the patient is unfit for surgery or bladder preservation is preferred. Currently data are still inadequate to allow formulation of definitive recommendations, and larger and higher quality studies of salvage intravesical therapies are urgently required. PMID- 27617553 TI - Low cost silicone renal replicas for surgical training - technical note. AB - OBJECTIVE: The aim of this brief report was to present and evaluate workflow of preparation of lowcost individual silicone replicas of kidneys for laparoscopic training and surgical simulation of difficult nephron sparing surgeries. METHODS: The work flow consists of four steps: 1.Image segmentation; 2.Casting mould designing; 3.Manufacturing of casting mould; 4.Silicone replica casting. To evaluate the cost and time required to execute the presented method, authors prepared 5 silicone models for 5 consecutive patients undergoing laparoscopic kidney tumorectomy due to renal cell cancer. RESULTS: Average times of image segmentation, casting mould design, casting mould printing and pouring of silicon replicas were 94 min, 22 min, 14 h and 30 min, respectively. Average costs of casting mould printing and casting of silicon replica were 14.4$ and 7.4$ respectively. CONCLUSION: The presented technique is simple to perform and beyond basic 3D printer it does not require any other expensive equipment. The final silicone model reproduces shape and elasticity of the living organ and has similar mechanical strength. These properties of silicone replica in combination with the presented technique can be used to prepare other artificial organs, ready for a simulation of treatment. PMID- 27617554 TI - A new case report of urinary tract infection due to KPC-3-producing klebsiella pneumoniae (ST258) in Spain. AB - OBJECTIVE: We describe the characterization of a new isolated in Spain of Klebsiella pneumoniae ST258 producing KPC-3, carbapenems non-susceptible, recovered from a sample of urine from a patient with urinary tract infection and no history of carbapenems exposure. METHODS: After the isolation, identification of K. pneumoniae was performed by biochemical tests and mass spectrometry. The carbapenems susceptibility testing was performed by microdilution and E-test in cation-adjusted Mueller-Hinton. The study was completed by Rapidec(r) Carba NP. In order to determine the genetic basis of resistance to carbapenems we used Xpert(r) Carba-R for carbapenemase type and subtype was subsequently analyzed by amplification by PCR and sequencing. RESULT: We demonstrated by MLST that the strain belonged to the clone of high-risk ST258. CONCLUSIONS: This is the first characterization, in our media, of a clinical isolated of K. pneumoniae ST258 producing KPC-3 and no history of carbapenems exposure. PMID- 27617556 TI - Male Pseudohermaphroditism: Ambiguous genitalia. PMID- 27617555 TI - [Complete response to tyrosine kinase inhibitors in metastatic renal cancer. Report of four cases]. AB - OBJECTIVSE: To describe the complete responses in our patients with metastatic renal cancer treated with tyrosine kinase inhibitors. MATERIAL AND METHODS: Between June 2007 and December 2014 we treated in our department 43 patients with metastatic renal cancer with antiangiogenic drugs. RESULTS: 9.3% (4/43) of the patients treated with antiangiogenic drugs obtained complete response according to RECIST 1.1 criteria. In 3 of the 4 patients, complete response was obtained during the first-line treatment with sunitinib at doses of 50 mgr/day in a 4/2 scheme and the remaining patient obtained it with second line axitinib at doses of 10 mgr/day. CONCLUSIONS: Tyrosine kinase inhibitors can induce complete responses in patients with metastatic renal cancer. Discontinuation of treatment with tyrosine kinase inhibitors after a complete response may be an option. PMID- 27617557 TI - Perirrenal presentation of extranodal Rosai-Dorfman disease. PMID- 27617558 TI - Enzalutamide as monotherapy for advanced prostate cancer: why not? AB - OBJECTIVES: Prostate cancer (PCa) is an androgen-dependent disease. In some cases, the tumor progresses despite castration levels of serum testosterone, turning into the lethal phenotype of castration-resistant prostate cancer (CRPC), still driven by androgens and requiring the androgen receptor as a driver and responsible for progression. Enzalutamide, an androgen receptor inhibitor, is indicated for the treatment of metastatic CRPC, asymptomatic or mildly symptomatic, after failure of androgen deprivation. In both clinical trials that led to its approval, Enzalutamide was administered with an LHRH analog, setting the "standard of care" for its use. In this article we evaluate the available evidence and theory on the use of Enzalutamide as monotherapy. METHODS: Androgen deprivation well-known adverse events, together with the fact that its clinical benefit is moderate and the evidence strength is weak, and the direct negative impact on the common chronic conditions affecting this age-group led to investigation of Enzalutamide without LHRH analogs. RESULTS: There are clinical trials on Enzalutamide monotherapy for hormone-sensitive prostate cancer with favourable outcomes, and there are also two ongoing studies in different advanced PCa scenarios, the PROSPER and EMBARK trials. It would be up to now a safe alternative, with less toxicity and lower costs. CONCLUSION: It is mandatory to validate these early results on the use on Enzalutamide monotherapy for advanced prostate cancer, hormone-sensitive or castration resistant, metastatic or not, but in the meantime, we wonder, why not? PMID- 27617559 TI - A Brief Version of the Unhelpful Thoughts and Beliefs About Stuttering Scales: The UTBAS-6. AB - Purpose: A significant proportion of adults who stutter experience anxiety in social and speaking situations. The Unhelpful Thoughts and Beliefs About Stuttering (UTBAS) scales provide a comprehensive measure of the unhelpful cognitions associated with social anxiety in stuttering. However, reducing the number of UTBAS items would make it ideal as a brief screening instrument. Therefore, the aim of the present study was to develop a brief version of the full UTBAS scales. Method: The 66-item UTBAS scales were completed by 337 adults who stutter. Item reduction was used to determine a smaller set of items that could adequately reproduce the total score for each full UTBAS scale. Results: Item reduction resulted in the inclusion of six items for the brief UTBAS-6 scales. Decile ranges for scores on the brief UTBAS-6 provide reliable estimates of the full UTBAS scores and valuable clinical information about whether a psychological assessment is warranted. Conclusions: The brief UTBAS-6 provides a reliable and efficient means of screening the unhelpful thoughts and beliefs associated with speech-related anxiety among adults who stutter. Referral for a psychological assessment is recommended in cases where the UTBAS total score falls in or above the fifth decile. PMID- 27617562 TI - Is There Inequity in Hospital Care Among Patients With Acute Coronary Syndrome Who Are Proficient and Not Proficient in English Language?: Analysis of the SNAPSHOT ACS Study. AB - BACKGROUND: The provision of equitable acute coronary syndrome (ACS) care in Australia and New Zealand requires an understanding of the sources of variation in the provision of this care. OBJECTIVE: The aim of this study was to compare the variation in care and outcomes between ACS patients with limited English proficiency (LEP) and English proficiency (EP) admitted to Australian and NZ hospitals. METHODS: Data were collected from 4387 suspected/confirmed ACS patients from 286 hospitals between May 14 and 27, 2012, who were followed for 18 months. We compared hospital care and outcomes according to the proficiency of English using logistic regressions. RESULTS: The 294 LEP patients were older (70.9 vs 66.3 years; P < .001) and had higher prevalence of hypertension (71.1% vs 62.8%; P = .004), diabetes (40.5% vs 24.3%; P < .001), and renal impairment (16.3% vs 11.1%; P = .007) compared with the 4093 EP patients. Once in hospital, there was no difference in receipt of percutaneous coronary intervention (57.0% vs 55.4%; P = .78) or coronary artery bypass graft surgery (10.5% vs 11.5%; P = .98). After adjustment for medical history, there were no significant differences (P > .05) between the 2 groups in the risk of major adverse cardiovascular events and/or all-cause death during the index admission and from index admission to 18 months. CONCLUSIONS: These results suggest that LEP patients admitted to Australian or New Zealand hospitals with suspected ACS may not experience inequity in hospital care and outcomes. PMID- 27617563 TI - Psychometrics of the Zarit Burden Interview in Caregivers of Patients With Heart Failure. AB - BACKGROUND: Identification of family caregivers who are burdened by the caregiving experience is vital to prevention of poor outcomes associated with caregiving. The Zarit Burden Interview (ZBI), a well-known measure of caregiving burden in caregivers of patients with dementia, has been used without being validated in caregivers of patients with heart failure (HF). PURPOSE: The purpose of this study is to examine the reliability and validity of the ZBI in caregivers of patients with HF. METHODS: A total of 124 primary caregivers of patients with HF completed survey questionnaires. Caregiving burden was measured by the ZBI. Reliability was examined using Cronbach's alpha and item-total/item-item correlations. Convergent validity was examined using correlations with the Oberst Caregiving Burden Scale. Construct validity was demonstrated by exploratory factor analysis and known hypothesis testing (ie, the hypothesis of the association between caregiving burden and depressive symptoms). RESULTS: Cronbach's alpha for the ZBI was .921. The ZBI had good item-total (r = 0.395 0.764) and item-item (mean r = 0.365) correlations. Significant correlations between the ZBI and the Oberst Caregiving Burden Scale (r = 0.466 for the caregiving time subscale and 0.583 for the caregiving task difficulty subscale; P < .001 for both) supported convergent validity. Four factors were identified (ie, consequences of caregiving, patient's dependence, exhaustion with caregiving and uncertainty, and guilt and fear for the patient's future) using factor analysis, which are consistent with previous studies. Caregivers with high burden scores had significantly higher depressive symptoms than did caregivers with lower burden scores (7.0 +/- 6.8 vs 3.1 +/- 4.3; P < .01). CONCLUSION: The findings provide evidence that the ZBI is a reliable and valid measure for assessing burden in caregivers of patients with HF. PMID- 27617565 TI - Perceptions and Acceptability of Receiving SMS Self-care Messages in Chinese Patients With Heart Failure: An Inpatient Survey. AB - BACKGROUND: Self-care is critical for postdischarge heart failure (HF) patients. Short message service (SMS) is a promising way to promote HF self-care. OBJECTIVE: The aim of this study is to investigate knowledge status in Chinese HF patients, as well as the acceptance of SMS as a way to improve self-care. METHODS: A survey using a self-developed questionnaire was conducted in patients with decompensated HF 2 days before discharge. RESULTS: A total of 540 patients completed the survey. Among them, only 69.8% and 63.3% of patients were aware of their HF status and medication regimen, respectively. A total of 95.6% patients were willing to receive SMS. Patient himself/herself, caregiver, or both patient and caregiver were almost equally selected as the preferred receiver of SMS. Educational and/or reminder SMS was considered "very helpful" by 50.2% of the patients as a way of promoting self-care, similar to that of telephone education and brochure education. "Take your medicine", "avoid getting flu," and "keep follow-up" were regarded as the most important self-care contents, whereas "weigh yourself every day" and "restrict fluid intake" were considered the least important. CONCLUSION: As a way of promoting HF self-care, SMS intervention combining educational and reminder function might be well accepted by HF patients in China. The status of HF, medication, weight control, and fluid restriction should be emphasized during the practice. Caution should be drawn as the survey was not tested elsewhere. Further clinical trials would be conducted to examine the effect of SMS intervention on self-care behaviors and outcomes of HF patients. PMID- 27617566 TI - Assessing Overreaching With Heart-Rate Recovery: What Is the Minimal Exercise Intensity Required? AB - PURPOSE: Faster heart-rate recovery (HRR) after high to maximal exercise (>=90% of maximal heart rate) has been reported in athletes suspected of functional overreaching (f-OR). This study investigated whether this response would also occur at lower exercise intensity. METHODS: Responses of HRR and rating of perceived exertion (RPE) were compared during an incremental intermittent running protocol to exhaustion in 20 experienced male triathletes (8 control subjects and 13 overload subjects led to f-OR) before and immediately after an overload training period and after a 1-wk taper. RESULTS: Both groups demonstrated an increase in HRR values immediately after the training period, but this change was very likely to almost certainly larger in the f-OR group at all running intensities (large to very large differences, eg, +16 +/- 7 vs +3 +/- 5 beats/min, in the f-OR and control groups at 11 km/h, respectively). The highest between-groups differences in changes in HRR were reported at 11 km/h (13 +/- 4 beats/min) and 12 km/h (10 +/- 6 beats/min). A concomitant increase in RPE at all intensities was reported only in the f-OR group (large to extremely large differences, +2.1 +/- 1.5 to +0.7 +/- 1.5 arbitrary units). CONCLUSION: These findings confirm that faster HRR does not systematically predict better physical performance. However, when interpreted in the context of the athletes' fatigue state and training phase, HRR after submaximal exercise may be more discriminant than HRR measures taken after maximal exercise for monitoring f-OR. These findings may be applied in practice by regularly assessing HRR after submaximal exercise (ie, warm-up) for monitoring endurance athletes' responses to training. PMID- 27617564 TI - Caregiver Well-being and Patient Outcomes in Heart Failure: A Meta-analysis. AB - BACKGROUND: Despite evidence from the broader caregiving literature about the interdependent nature of the caregiving dyad, few studies in heart failure (HF) have examined associations between caregiver and patient characteristics. OBJECTIVE: The aim of this study is to quantitatively synthesize the relationships between caregiver well-being and patient outcomes. METHODS: The MEDLINE, PsycINFO, and CINAHL databases were searched for studies of adult HF patients and informal caregivers that tested the relationship between caregiver well-being (perceived strain and psychological distress) and patient outcomes of interest. Summary effects across studies were estimated using random effects meta analysis following the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. RESULTS: A total of 15 articles meeting inclusion criteria were included in the meta-analysis. Taking into account differences across studies, higher caregiver strain was associated significantly with greater patient symptoms (Fisher z = 0.22, P < .001) and higher caregiver strain was associated significantly with lower patient quality of life (Fisher z = -0.36, P < .001). Relationships between caregiver psychological distress and both patient symptoms and quality of life were not significant. Although individual studies largely found significant relationships between worse caregiver well-being and higher patient clinical event-risk, these studies were not amenable to meta analysis because of substantial variation in event-risk measures. CONCLUSIONS: Clinical management and research approaches that acknowledge the interdependent nature of the caregiving dyad hold great potential to benefit both patients and caregivers. PMID- 27617567 TI - Tuberous Sclerosis Complex: A Roadmap for Future Research. AB - Investigators from the NINDS and the Tuberous Sclerosis Alliance sponsored a workshop in March 2015, which joined basic scientists and clinicians with expertise in various aspects of Tuberous Sclerosis Complex (TSC), in order to assess the current state of TSC research and to set future goals. PMID- 27617568 TI - Layer-by-Layer Assembled Films of Perylene Diimide- and Squaraine-Containing Metal-Organic Framework-like Materials: Solar Energy Capture and Directional Energy Transfer. AB - We demonstrate that thin films of metal-organic framework (MOF)-like materials, containing two perylenediimides (PDICl4, PDIOPh2) and a squaraine dye (S1), can be fabricated by layer-by-layer assembly (LbL). Interestingly, these LbL films absorb across the visible light region (400-750 nm) and facilitate directional energy transfer. Due to the high spectral overlap and oriented transition dipole moments of the donor (PDICl4 and PDIOPh2) and acceptor (S1) components, directional long-range energy transfer from the bluest to reddest absorber was successfully demonstrated in the multicomponent MOF-like films. These findings have significant implications for the development of solar energy conversion devices based on MOFs. PMID- 27617569 TI - Structural basis of haem-iron acquisition by fungal pathogens. AB - Pathogenic microorganisms must cope with extremely low free-iron concentrations in the host's tissues. Some fungal pathogens rely on secreted haemophores that belong to the Common in Fungal Extracellular Membrane (CFEM) protein family, to extract haem from haemoglobin and to transfer it to the cell's interior, where it can serve as a source of iron. Here we report the first three-dimensional structure of a CFEM protein, the haemophore Csa2 secreted by Candida albicans. The CFEM domain adopts a novel helical-basket fold that consists of six alpha helices, and is uniquely stabilized by four disulfide bonds formed by its eight signature cysteines. The planar haem molecule is bound between a flat hydrophobic platform located on top of the helical basket and a peripheral N-terminal 'handle' extension. Exceptionally, an aspartic residue serves as the CFEM axial ligand, and so confers coordination of Fe3+ haem, but not of Fe2+ haem. Histidine substitution mutants of this conserved Asp acquired Fe2+ haem binding and retained the capacity to extract haem from haemoglobin. However, His-substituted CFEM proteins were not functional in vivo and showed disturbed haem exchange in vitro, which suggests a role for the oxidation-state-specific Asp coordination in haem acquisition by CFEM proteins. PMID- 27617574 TI - Disruption of the RP-MDM2-p53 pathway accelerates APC loss-induced colorectal tumorigenesis. AB - Inactivation of the adenomatous polyposis coli (APC) tumor suppressor is frequently found in colorectal cancer. Loss of APC function results in deregulation of the Wnt/beta-catenin signaling pathway causing overexpression of the c-MYC oncogene. In lymphoma, both p19ARF and ribosomal proteins RPL11 and RPL5 respond to c-MYC activation to induce p53. Their role in c-MYC-driven colorectal carcinogenesis is unclear, as p19ARF deletion does not accelerate APC loss-triggered intestinal tumorigenesis. To determine the contribution of the ribosomal protein (RP)-murine double minute 2 (MDM2)-p53 pathway to APC loss induced tumorigenesis, we crossed mice bearing MDM2C305F mutation, which disrupts RPL11- and RPL5-MDM2 binding, with Apcmin/+ mice, which are prone to intestinal tumor formation. Interestingly, loss of RP-MDM2 binding significantly accelerated colorectal tumor formation while having no discernable effect on small intestinal tumor formation. Mechanistically, APC loss leads to overexpression of c-MYC, RPL11 and RPL5 in mouse colonic tumor cells irrespective of MDM2C305F mutation. However, notable p53 stabilization and activation were observed only in Apcmin/+;Mdm2+/+ but not Apcmin/+;Mdm2C305F/C305F colon tumors. These data establish that the RP-MDM2-p53 pathway, in contrast to the p19ARF-MDM2-p53 pathway, is a critical mediator of colorectal tumorigenesis following APC loss. PMID- 27617577 TI - RN1, a novel galectin-3 inhibitor, inhibits pancreatic cancer cell growth in vitro and in vivo via blocking galectin-3 associated signaling pathways. AB - Galectin-3 (Gal-3) has been implicated in pancreatic ductal adenocarcinoma (PDAC), and its candidacy as a therapeutic target has been evaluated. Gal-3 is widely upregulated in tumors, and its expression is associated with the development and malignancy of PDAC. In the present study, we demonstrate that a polysaccharide, RN1, purified from the flower of Panax notoginseng binds to Gal-3 and suppresses its expression. In addition, RN1 markedly inhibits PDAC cells growth in vitro, in vivo and in patient-derived xenografts. Mechanistically, RN1 binds to epidermal growth factor receptor (EGFR) and Gal-3, thereby disrupting the interaction between Gal-3 and EGFR and downregulating extracellular-related kinase (ERK) phosphorylation and the transcription factor of Gal-3, Runx1 expression. Inhibiting the expression of Runx1 by RN1, suppresses Gal-3 expression and inactivates Gal-3-associated signaling pathways, including the EGFR/ERK/Runx1, BMP/smad/Id-3 and integrin/FAK/JNK signaling pathways. In addition, RN1 can also bind to bone morphogenetic protein receptors (BMPR1A and BMPR2) and block the interaction between Gal-3 and the BMPRs. Thus, our results suggest that a novel Gal-3 inhibitor RN1 may be a potential candidate for human PDAC treatment via multiple targets and multiple signaling pathways. PMID- 27617576 TI - Epithelial-mesenchymal transition of ovarian cancer cells is sustained by Rac1 through simultaneous activation of MEK1/2 and Src signaling pathways. AB - Epithelial-mesenchymal transition (EMT) is regarded as a crucial contributing factor to cancer progression. Diverse factors have been identified as potent EMT inducers in ovarian cancer. However, molecular mechanism sustaining EMT of ovarian cancer cells remains elusive. Here we show that the presence of SOS1/EPS8/ABI1 complex is critical for sustained EMT traits of ovarian cancer cells. Consistent with the role of SOS1/EPS8/ABI1 complex as a Rac1-specific guanine nucleotide exchange factor, depleting Rac1 results in the loss of most of mesenchymal traits in mesenchymal-like ovarian cancer cells, whereas expressing constitutively active Rac1 leads to EMT in epithelial-like ovarian cancer cells. With the aid of clinically tested inhibitors targeting various EMT-associated signaling pathways, we show that only combined treatment of mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2) and Src inhibitors can abolish constitutively active Rac1-led EMT and mesenchymal traits displayed by mesenchymal-like ovarian cancer cells. Further experiments also reveal that EMT can be induced in epithelial-like ovarian cancer cells by co-expressing constitutively active MEK1 and Src rather than either alone. As the activities of Erk and Src are higher in ovarian cancer cells with constitutively active Rac1, we conclude that Rac1 sustains ovarian cancer cell EMT through simultaneous activation of MEK1/2 and Src signaling pathways. Importantly, we demonstrate that combined use of MEK1/2 and Src inhibitors effectively suppresses development of intraperitoneal xenografts and prolongs the survival of ovarian cancer-bearing mice. This study suggests that cocktail of MEK1/2 and Src inhibitors represents an effective therapeutic strategy against ovarian cancer progression. PMID- 27617575 TI - Wnt signaling in cancer. AB - Wnt signaling is one of the key cascades regulating development and stemness, and has also been tightly associated with cancer. The role of Wnt signaling in carcinogenesis has most prominently been described for colorectal cancer, but aberrant Wnt signaling is observed in many more cancer entities. Here, we review current insights into novel components of Wnt pathways and describe their impact on cancer development. Furthermore, we highlight expanding functions of Wnt signaling for both solid and liquid tumors. We also describe current findings how Wnt signaling affects maintenance of cancer stem cells, metastasis and immune control. Finally, we provide an overview of current strategies to antagonize Wnt signaling in cancer and challenges that are associated with such approaches. PMID- 27617578 TI - Upregulation of Flt3 is a passive event in Hoxa9/Meis1-induced acute myeloid leukemia in mice. AB - HOXA9, MEIS1 and FLT3 are genes frequently upregulated in human acute myeloid leukemia. Hoxa9 and Meis1 also cooperate to induce aggressive AML with high Flt3 expression in mice, suggesting an important role for Flt3 in Hoxa9/Meis1-induced leukemogenesis. To define the role of Flt3 in AML with high Hoxa9/Meis1, we treated mice with Hoxa9/Meis1-induced AML with the Flt3 inhibitor AC220, used an Flt3-ligand (FL-/-) knockout model, and investigated whether overexpression of Flt3 could induce leukemia together with overexpression of Hoxa9. Flt3 inhibition by AC220 did not delay AML development in mice transplanted with bone marrow cells overexpressing Hoxa9 and Meis1. In addition, Hoxa9/Meis1 cells induced AML in FL-/- mice as rapid as in wild-type mice. However, FL-/- mice had reduced organ infiltration compared with wild-type mice, suggesting some Flt3-dependent effect on leukemic invasiveness. Interestingly, leukemic Hoxa9/Meis1 cells from sick mice expressed high levels of Flt3 regardless of presence of its ligand, showing that Flt3 is a passive marker on these cells. In line with this, combined engineered overexpression of Flt3 and Hoxa9 did not accelerate the progression to AML. We conclude that the Hoxa9- and Meis1-associated upregulation of Flt3 is not a requirement for leukemic progression induced by Hoxa9 and Meis1. PMID- 27617579 TI - FKBP12 enhances sensitivity to chemotherapy-induced cancer cell apoptosis by inhibiting MDM2. AB - The FK506-binding protein 12 (FKBP12) is a cytoplasmic protein and has been reported to possess multiple functions in signaling transduction based on its interaction with different cellular targets. Here, we report that FKBP12 interacts with oncoprotein MDM2 and induces MDM2 degradation. We demonstrate that FKBP12 degrades MDM2 through binding to MDM2 protein, disrupting MDM2/MDM4 interaction and inducing MDM2 self-ubiquitination. The FKBP12-mediated MDM2 degradation was significantly enhanced when the transfected MDM2 was localized in the cytoplasm. The endogenous MDM2, when it was induced by p53 subjecting to DNA damaging stimuli such as treatment with doxorubicin, was also significantly inhibited by FKBP12. This is due to translocation of p53-induced MDM2 from the nucleus to the cytoplasm, which facilitates interaction with cytoplasmic FKBP12. Furthermore, the enhanced level of MDM2 following p53 activation in nutlin-3 treated cells was also inhibited by FKBP12. The FKBP12-mediated downregulation of MDM2 in response to doxorubicin or nutlin-3 results in continuing and constitutive activation of p53, inhibition of XIAP and sensitization of cancer cells to apoptosis. These results identify a novel function for FKBP12 in downregulating MDM2, which directly enhances sensitivity of cancer cells to chemotherapy and nutlin-3 treatment. PMID- 27617584 TI - Silicon/Organic Heterojunction for Photoelectrochemical Energy Conversion Photoanode with a Record Photovoltage. AB - Silicon (Si) is a good photon absorption material for photoelectrochemical (PEC) conversion. Recently, the relatively low photovoltage of Si-based PEC anode is one of the most significant factors limiting its performance. To achieve a high photovoltage in PEC electrode, both a large barrier height and high-quality surface passivation of Si are indispensable. However, it is still challenging to induce a large band bending and passivate Si surface simultaneously in Si-based PEC photoanodes so far, which hinders their performance. Here, we develop a simple Si/poly(3,4-ethylenedioxythiophene):polystyrenesulfonate (PEDOT:PSS) heterojunction with large band banding and excellent surface passiviation for efficient PEC conversion. A chemically modified PEDOT:PSS film acts as both a surface passiviation layer and an effective catalyst simultaneously without sacrificing band bending level. A record photovoltage for Si-based PEC photoanodes as high as 657 mV is achieved via optimizing the PEDOT:PSS film fabrication process. The density of electron state (DOS) measurement is utilized to probe the passivation quality of the organic/inorganic heterojunction, and a low DOS is found in the Si/PEDOT:PSS heterojunction, which is in accordance with the photovoltage results. The low-temperature solution-processed Si/organic heterojunction photoanode provides a high photovoltage, exhibiting the potential to be the next-generation economical photoanode in PEC applications. PMID- 27617585 TI - Realistic multi-cellular dosimetry for 177Lu-labelled antibodies: model and application. AB - Current preclinical dosimetric models often fail to take account of the complex nature of absorbed dose distribution typical of in vitro clonogenic experiments in targeted radionuclide therapy. For this reason, clonogenic survival is often expressed as a function of added activity rather than the absorbed dose delivered to cells/cell nuclei. We designed a multi-cellular dosimetry model that takes into account the realistic distributions of cells in the Petri dish, for the establishment of survival curves as a function of the absorbed dose. General purpose software tools were used for the generation of realistic, randomised 3D cell culture geometries based on experimentally determined parameters (cell size, cell density, cluster density, average cluster size, cell cumulated activity). A mixture of Monte Carlo and analytical approaches was implemented in order to achieve as accurate as possible results while reducing calculation time. The model was here applied to clonogenic survival experiments carried out to compare the efficacy of Betalutin(r), a novel 177Lu-labelled antibody radionuclide conjugate for the treatment of non-Hodgkin lymphoma, to that of 177Lu-labelled CD20-specific (rituximab) and non-specific antibodies (Erbitux) on lymphocyte B cells. The 3D cellular model developed allowed a better understanding of the radiative and non-radiative processes associated with cellular death. Our approach is generic and can also be applied to other radiopharmaceuticals and cell distributions. PMID- 27617580 TI - Ecotropic viral integration site 1, a novel oncogene in prostate cancer. AB - Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous cancer in men in the western world. Mutations in tumor suppressor genes and in oncogenes are important for PCa progression, whereas the role of stem cell proteins in prostate carcinogenesis is insufficiently examined. This study investigates the role of the transcriptional regulator Ecotropic Viral Integration site 1 (EVI1), known as an essential modulator of hematopoietic and leukemic stem cell biology, in prostate carcinogenesis. We show that in healthy prostatic tissue, EVI1 expression is confined to the prostate stem cell compartment located at the basal layer, as identified by the stem cell marker CD44. Instead, in a PCa progression cohort comprising 219 samples from patients with primary PCa, lymph node and distant metastases, EVI1 protein was heterogeneously distributed within samples and high expression is associated with tumor progression (P<0.001), suggesting EVI1 induction as a driver event. Functionally, short hairpin RNA-mediated knockdown of EVI1 inhibited proliferation, cell cycle progression, migratory capacity and anchorage-independent growth of human PCa cells, while enhancing their apoptosis sensitivity. Interestingly, modulation of EVI1 expression also strongly regulated stem cell properties (including expression of the stem cell marker SOX2) and in vivo tumor initiation capacity. Further emphasizing a functional correlation between EVI1 induction and tumor progression, upregulation of EVI1 expression was noted in experimentally derived docetaxel-resistant PCa cells. Importantly, knockdown of EVI1 in these cells restored sensitivity to docetaxel, in part by downregulating anti-apoptotic BCL2. Together, these data indicate EVI1 as a novel molecular regulator of PCa progression and therapy resistance that may control prostate carcinogenesis at the stem cell level. PMID- 27617586 TI - Analysis of Polymorphism rs1900004 in Atonal bHLH Transcription Factor 7 in Saudi Patients with Primary Open Angle Glaucoma. AB - AIMS: To investigate the association between the rs1900004 polymorphism in the atonal bHLH transcription factor 7 (ATOH7) gene and primary open angle glaucoma (POAG) in Saudi patients. METHODS: Eighty-seven unrelated POAG cases and 94 unrelated control subjects of Saudi origin were genotyped utilizing a TaqMan(r) assay. The association between mutant genotypes and POAG and its related clinical indices was investigated. RESULTS: The genotype and allele frequencies of the polymorphism in ATOH7 did not show any statistically significant association with POAG compared to controls. The minor allele frequency was 0.32 in both cases and controls. None of the demographic, systemic diseases nor glaucoma-specific clinical indices such as intraocular pressure (IOP), cup/disc ratio, and number of antiglaucoma medication, showed any significant association with genotypes. Binary logistic regression analysis (adjusted for age and gender) showed that age was a marginally significant risk factor for the development of glaucoma (adjusted odds ratio = 1.1; 95% confidence interval = 1.079-1.158; p < 0.0001). CONCLUSIONS: The study did not detect any direct link between genotype/allele frequency of rs1900004 in ATOH7 and POAG or its related clinical indices such as IOP and cup/disc ratio indicating that this polymorphism is not a risk factor for POAG in a Saudi cohort. PMID- 27617589 TI - Competing Roles of Substrate Composition, Microstructure, and Sustained Strontium Release in Directing Osteogenic Differentiation of hMSCs. AB - Strontium releasing bioactive ceramics constitute an important class of biomaterials for osteoporosis treatment. In the present study, we evaluated the synthesis, phase assemblage, and magnetic properties of strontium hexaferrite, SrFe12O19, (SrFe) nanoparticles. On the biocompatibility front, the size- and dose-dependent cytotoxicity of SrFe against human mesenchymal stem cells (hMSCs) were investigated. After establishing their non-toxic nature, we used the strontium hexaferrite nanoparticles (SrFeNPs) in varying amount (x = 0, 10, and 20 wt %) to consolidate bioactive composites with hydroxyapatite (HA) by multi stage spark plasma sintering (SPS). Rietveld refinement of these spark plasma sintered composites revealed a near complete decomposition of SrFe12O19 to magnetite (Fe3O4) along with a marked increase in the unit cell volume of HA, commensurate with strontium-doped HA. The cytocompatibility of SrHA-Fe composites with hMSCs was assessed using qualitative and quantitative morphological analysis along with phenotypic and genotypic expression for stem cell differentiation. A marked decrease in the stemness of hMSCs, indicated by reduced vimentin expression and acquisition of osteogenic phenotype, evinced by alkaline phosphatase (ALP) and collagen deposition was recorded on SrHA-Fe composites in osteoinductive culture. A significant upregulation of osteogenic marker genes (Runx2, ALP and OPN) was detected in case of the SrHA-Fe composites, whereas OCN and Col IA expression were similarly high for baseline HA. However, matrix mineralization was elevated on SrHA-Fe composites in commensurate with the release of Sr2+ and Fe2+. Summarizing, the current work is the first report of strontium hexaferrite as a non-toxic nanobiomaterial. Also, SrHA-based iron oxide composites can potentially better facilitate bone formation, when compared to pristine HA. PMID- 27617590 TI - Probing Molecular Interactions in Functionalized Asymmetric Quaternary Ammonium Based Dicationic Ionic Liquids. AB - Electronic structure, binding energies, and spectral characteristics of functionalized asymmetric dicationic ionic liquids (DILs) composed of quaternary ammonium cations substituted with the ethoxyethyl and allyl/3 phenylpropyl/methoxyethoxyethyl/pentyl functionalities on two different nitrogen centers of the dication and the bis(trifluoromethanesulfonyl)imide (Tf2N-) anion were derived employing the dispersion-corrected density functional theory. DILs based on methoxyethoxyethyl-substituted cation reveal stronger binding toward the Tf2N- anion. The measured glass transition temperatures are found to be strongly dependent on the cation-anion binding facilitated through noncovalent interactions with dominant contributions from the electrostatics and hydrogen bonding. The manifestations of these interactions to vibrational spectra, in particular, to SO2 and CF3 stretchings in the complexes are presented. It has been demonstrated that the frequency down (red)-shift of the SO2 stretching in these DILs with varying substituent follows the order: methoxyethoxyethyl (35 cm 1) > allyl (23 cm-1) > pentyl (20 cm-1) > 3-phenylpropyl (5 cm-1), which is consistent with the strength of cation-anion binding. The CF3 stretching of the anion exhibits the frequency shift in the opposite direction with its hierarchy being reversed to that of SO2 stretchings; the largest upshift (blue shift) of 60 cm-1 was predicted for the DILs composed of 3-phenlpropyl substituted dications. The direction of such frequency shift has been rationalized through the difference molecular electron density maps in conjunction with the electron density at the bond critical point in the quantum theory of atoms in molecules. The underlying cation-anion binding has been analyzed through charge distribution analysis characterized in terms of molecular electrostatic potential topography. Furthermore, the observed decomposition temperatures of DILs are shown to correlate well with the maximum surface electrostatic potential parameters in quantum theory of atoms in molecules. PMID- 27617592 TI - Medicaid and Children's Hospitals-A Vital but Strained Double Helix for Children's Health Care. PMID- 27617593 TI - Drug Conjugation Affects Pharmacokinetics and Specificity of Kidney-Targeted Peptide Carriers. AB - Peptides play a crucial role as biological vectors for targeted drug delivery. In particular, in cases of specific receptor expression, peptides are highly potent carriers for drug targeting approaches. Kidney-targeted peptides require specific attention because of the necessity of fine-tuning their behavior with respect to extraction and retention in the complex architecture of the kidneys. To enable optimal carrier capacity and targeting specificity, this study focuses on pharmacokinetic profiles of different kidney-specific peptides and examines the impact of drug conjugation. gamma-Scintigraphy was used to compare the pharmacokinetics and specificity prior to and after drug conjugation of the model drug alpha-lipoic acid. The results revealed that drug conjugation dramatically affects the targeting specificity, in the worst case leading to a total loss of kidney specificity. Nevertheless, efficient drug transport was achieved with the novel kidney carrier (KKEEE)3K, even with a multiple-drug loading of alpha-lipoic acid after intraveous and intraperitoneal administration. In contrast to other peptidic molecules, (KKEEE)3K demonstrated its significant potential as a promising carrier candidate for kidney-targeted drug delivery to proximal tubule cells, especially for the treatment of severe kidney diseases. PMID- 27617588 TI - Lymphocyte-mediated Immune Regulation in Health and Disease: The Treg and gammadelta T Cell Co-conspiracy. AB - The significance of lymphocytes functioning to mediate immunological tolerance has garnered increasing appreciation during the last several decades. CD4+ CD25+ alpha/ beta T cells have arguably been the most extensively studied regulatory lymphocyte to date, perhaps owing to the dramatic phenotype observed mice and humans with mutated Foxp3. However, emerging studies suggest that the lineage of regulatory lymphocytes is quite robust. Most notably, while gammadelta T cells are more traditionally regarded as mediators of cytotoxic function, they are beginning to be regarded as potential negative regulators of immunity. While regulatory gamma/delta T cells may possess a degree of transcriptional overlap with 'classical Tregs', there remains less clarity in regard to the mechanisms driving the suppressive potential of these cells. In this review, I will discuss the role of Tregs in establishing tolerance in the steady state as well as disease, and how their accumulation and function may be modulated by myeloid cells in the local microenvironment. I will also discuss the necessity to extend our understanding of the regulatory nature of gammadelta T cells, which may lead to the unearthing of novel paradigms of immunity, perhaps most notably with respect to cancer. PMID- 27617594 TI - Home environments, physical activity, and energy expenditure among low-income overweight and obese women. AB - Ecologic models of physical activity identify multiple environmental domains that influence activity levels, including the home. This study examined aspects of the home environment associated with objective measures of physical activity in overweight and obese women. Study participants were recruited through three federally qualified health centers in rural southwest Georgia as part of a randomized controlled trial of a home-environment-focused weight gain prevention intervention. Data collected from February 2011 to December 2012 were from 301 participants who completed baseline interviews and wore accelerometers for 7 days. Most were African American (83.4%) and obese (50.5%) or morbidly obese with body mass index >=40 (35.6%). Mean age was 50.6 years. Participants were highly sedentary, with 7.9 hours of non-sedentary time per week, primarily in light activity. In a multivariate model, exercise equipment (p = .03), family support (p = .02), and full-time employment (p = .03) were positively associated with non sedentary time, whereas age (p = .003), living in a more rural area (p = .03), and having an exercise space (p = .01) were negatively associated. Home environments may be promising targets for programs aimed at increasing activity levels among overweight and obese women. PMID- 27617595 TI - Low-Concentration Eu2+-Doped SrAlSi4N7: Ce3+ Yellow Phosphor for wLEDs with Improved Color-Rendering Index. AB - Luminescence property of low-concentration Eu2+-doped SrAlSi4N7:Ce3+ yellow phosphor is reported in this paper. Three optical centers Ce1, Ce2, and Eu2 are observed in the phosphor. Deconvolution of emission spectrum confirms the three centers to be green (530 nm), yellow (580 nm), and red (630 nm), respectively. This property promises considerable improvement of color-rendering property of a white light-emitting diode (wLED). For example, color-rendering index (CRI) of wLED fabricated by combining a blue LED chip and SrAlSi4N7:0.05Ce3+,0.01Eu2+ phosphor reaches 88. A competitive energy transfer process between Ce1-Ce2 and Ce1-Eu2 is confirmed based on Inokuti-Hirayama formula. Ratio of energy transfer rate between Ce1-Ce2 and Ce1-Eu2 (WCe1-Eu2/WCe1-Ce2) is calculated to be 2.0. This result reveals the effect of Eu2+ concentration on quantity of green and red components in SrAlSi4N7:Ce3+,Eu2+ phosphor. PMID- 27617596 TI - Why rifampin (rifampicin) is a key component in the antibiotic treatment of hidradenitis suppurativa: a review of rifampin's effects on bacteria, bacterial biofilms, and the human immune system. AB - Combinations of rifampin and clindamycin or rifampin, metronidazole, and moxifloxcin have been reported as effective treatments for hidradenitis suppurativa (HS) Hurley Stage 1 and Hurley Stage 2. Clinical trials suggest that for stage 1 and mild stage 2 HS, clindamycin 300 mg twice daily and rifampin 300 mg twice daily for 10 weeks can substantially abate HS in ~80% of cases and remit HS in ~50% of cases. Another study notes use of rifampin-moxifloxacin metronidazole given for 6 weeks, dosed as rifampin (10 mg/kg once daily), moxifloxacin (400 mg daily), and metronidazole (500 mg thrice daily) with the metronidazole stopped at week 6. Rifampin and moxifloxacin were continued if the HS improved and side effects did not occur. Using this triple antibiotic regimen remission occurred in 100% Hurley Stage 1, 80% Hurly Stage 2, and 16.7 % of Hurley Stage 3 HS. The author typically gives HS clindamycin 300 mg and rifampin 300 mg, each twice daily, for 10 weeks and assesses if remission has occurred. If the patient has not achieved remission the author continues the regimen as long as the patient's clinical status continues to improve without side effects. The reasons why rifampin is so effective against HS have not been fully defined and might involve rifampin's (1) antibacterial effects (2) effects on bacterial biofilms (3) anti-inflammatory effects (4) effects against granulomas (5) and immunomodulatory effects on neutrophils. It is notable that rifampin, although not first line, is an effective treatment for Clostridium difficile, a pathogen that arises during treatment with clindamycin. Thus, rifampin enhances safety when rifampin and clindamycin are combined for the treatment of HS. PMID- 27617597 TI - Incontinentia Pigmenti presenting as a newborn eruption: two case presentations. AB - Linear vesicles or papules in a newborn can be a presenting sign of incontinentia pigmenti (IP). In this report, we present two cases of neonates with cutaneous manifestations of incontinentia pigmenti. In one case, mild peripheral eosinophilia was noted. No extra-cutaneous manifestations were noted otherwise in both cases after complete ophthalmological and neurological evaluations. These cases serve as a reminder for clinicians to consider IP in newborns presenting with linear vesicles or papules. PMID- 27617598 TI - Yellow hair following sequential application of bacitracin zinc and selenium sulfide: Report of acquired xanthotrichosis and review of yellow hair discoloration. AB - BackgroundAcquired yellow hair (xanthotrichosis) can result from the deposition of pigmented compounds on the hair shaft or from chemical modification of hair pigment and protein molecules.PurposeA white-haired 77-year-old woman who developed xanthotrichosis of her scalp hair following the sequential application of bacitracin zinc ointment and selenium sulfide 2.5% lotion is described and the causes of yellow hair discoloration are reviewed.Materials and methodsThe clinical features of a woman with acquired yellow hair discoloration are presented. Using PubMed and Google Scholar, the following terms were searched and relevant citations were assessed: bacitracin zinc, hair discoloration, selenium sulfide, xanthotrichosis, and yellow hair.ResultsYellow hair was observed on the scalp in areas treated with the following regimen: prior to bedtime, several areas of the scalp were treated with a single application of bacitracin zinc ointment. The next morning, selenium sulfide 2.5% lotion was applied and then rinsed from the scalp during showering. Yellow hair discoloration was apparent in co-treated areas immediately following rinsing; the discoloration gradually faded over 2-5 days with regular shampooing.ConclusionsAcquired yellow hair shaft discoloration has been reported secondary to multiple etiologies, including environmental and occupational exposures, iatrogenic causes (including topical and systemic drugs) and protein-calorie malnutrition. To this list, we add yellow discoloration of white scalp hair due to application of selenium sulfide following topical use of bacitracin zinc in the affected areas as an unexpected adverse effect that may occur in individuals with white hair. PMID- 27617599 TI - Cryptococcal cellulitis on the shin of an immunosuppressed patient. AB - Cryptococcus neoformans is a common fungus found throughout the environment that causes opportunistic disease in immunocompromised individuals. Infection of humans with C neoformans usually manifests as lung disease through inhalation of spores or meningoencephalitis by involvement of the central nervous system. Rarely, dissemination in the form of cutaneous lesions can occur in individuals with long term immunosuppression. We present a patient with C. neoformans manifesting as cellulitis with focal segmental glomerulosclerosis treated with corticosteroids. Because of the mortality associated with disseminated cryptococcosis, early identification, especially of atypical cutaneous presentations is critical from a dermatological perspective. PMID- 27617600 TI - Myxofibrosarcoma presenting as an exophytic, multi-lobed nodule on the leg. AB - Myxofibrosarcoma may present as a dermal or subcutaneous nodule, often on the extremity of an elderly patient. We present a case of myxofibrosarcoma on the lower leg of a 77-year-old man, which illustrates the deeply infiltrative growth pattern of these tumors, as well as the potential for superficial biopsies to show lower grade histopathologic features than subsequent excision specimens. PMID- 27617601 TI - Unusual location of median raphe cyst presenting as perianal polyp: a case report. AB - Median raphe cysts (MRC) are uncommon, benign congenital lesions that may present anywhere in the midline between the urinary meatus and the anus, with the shaft of the penis and the glans penis being the most common sites. We report a 52-year old man with median raphe cyst unusually located in perianal region and treated by surgical excision. PMID- 27617602 TI - Pyodermatitis vegetans of the vulva. AB - Pyodermatitis vegetans (PV) is a rare inflammatory dermatosis of unknown etiology and difficult diagnosis characterized by vesiculopustular, exudative, and vegetating plaques usually localized in the axillary, genital, and oral region. It bears similarities to pemphigus vegetans but clinical history, histology, and immunofluorescence help confirm the diagnosis. Pyodermatitis vegetans is often associated with an underlying gastrointestinal disorder, especially ulcerative colitis. No standardized treatment plan is available for PV. Its evolution tends to follow the progression of the underlying disorder. We report a patient with vulvar PV with good response to systemic antibiotics and corticosteroids. PMID- 27617603 TI - Pseudoxanthoma Elasticum: report of a case with a novel gene mutation. AB - Pseudoxanthoma Elasticum (PXE) is a rare autosomal recessive disorder characterized by progressive calcification and fragmentation of elastic fibers in the skin, eyes, and cardiovascular system. PXE is caused by mutations in the ABCC6 gene but the specific pathophysiology of this condition remains unknown. We present a case of a patient who was diagnosed with PXE after experiencing vision loss following minor ocular trauma. Our patient had angioid streaks in her right eye, skin laxity of the bilateral dorsal hands, and yellow papules coalescing on the posterior neck. The diagnosis of PXE was confirmed by histopathological examination. PCR amplification of the patient's ABCC6 gene demonstrated a novel gene mutation that is believed to be pathogenic. Patients with PXE are at an increased risk of visual and potentially life-threatening cardiovascular complications. Early diagnosis provides the patient a greater chance of reducing associated morbidity and mortality. PMID- 27617604 TI - Chronic, severe onychocryptosis successfully treated with nail tube splinting in a 13-year-old girl with multiple prior failed matricectomies. AB - Onychocryptosis, also known as ingrown toenail, is caused by growth of the lateral edge of the nail into the nail fold. This results in inflammation of the invaded tissue. It is a common problem with ~70% of cases occurring in people between the ages of 12-30 years and causes significant discomfort, pain, and restriction in activity [1]. There is no standard treatment for onychocryptosis and numerous methods have been used, from conservative approaches such as proper nail trimming techniques to more invasive surgical procedures. All techniques risk the possibility of damage to the nail apparatus, prolonged healing time, and recurrence of disease.We describe a successful case of bilateral nail tube splinting in a pediatric patient with recurrent, severe onychocryptosis and history of multiple matricectomies. PMID- 27617606 TI - An atrophic plaque on the breast six years after breast reconstruction surgery. AB - Necrobiosis lipoidica (NL) is a cutaneous disease entity that typically manifests as atrophic yellow plaques with telangiectasias on the anterior tibial region. Although NL is commonly associated with diabetes mellitus, the role of trauma in disease development is less commonly emphasized. The relationship between NL and the Kobner phenomenon has been established, as a few cases of NL occurring in surgical scars have been reported in the literature. We report the first case of NL occurring in a mastectomy scar on the breast in a non-diabetic female, and explore the relationship between NL, diabetes mellitus, and trauma. PMID- 27617605 TI - Segmental lesions along blaschko's lines in an elderly man. AB - Darier disease (DD) is an autosomal dominant genodermatosis characterized by multiple keratotic and crusted papules over seborrheic areas, along with a variable involvement of oral mucosa, palmoplantar region, and nails. Segmental subtypes (type 1 and 2) are uncommon clinically limited forms of DD that usually present at middle age with few cutaneous lesions following Blaschko's lines. We report a case of extensive multi segmental DD type 1 that developed in an elderly man, an unusual clinical onset of DD that dermatologists should bear in mind. PMID- 27617607 TI - Regorafenib- associated panniculitis. AB - Regorafenib is a second-generation multikinase inhibitor that is approved for the treatment of metastatic colon cancer and advanced gastrointestinal stromal tumors. Hand-foot skin reaction, alopecia, and oral mucositis are well established side effects of this medication. Herein, we discuss a 60-year-old woman who developed a lobular and septal granulomatous panniculitis after six months of therapy with regorafenib. Biopsy demonstrated focal lobular and septal granulomatous inflammation admixed with septal fibrosis and lobular lymphohistiocytic infiltrate associated with fat necrosis. To our knowledge, regorafenib-induced panniculitis has not been previously described. Increased awareness of this presentation can facilitate more timely diagnosis and treatment. PMID- 27617608 TI - Morbilliform eruption related to eltrombopag: emerging data on the cutaneous toxicity of thrombopoietin receptor agonists. AB - Eltrombopag is a thrombopoietin mimetic used for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia, hepatitis C patients undergoing antiviral therapy, and thrombocytopenia secondary to aplastic anemia that is refractory to immunosuppressive therapy. We report a case of a 25 year-old man with a history of aplastic anemia who presented with fever and a monomorphic papular rash. Subsequent labs, biopsy, and clinical course favored drug-induced cutaneous toxicity, with eltrombopag as the likely culprit. Eltrombopag is generally well-tolerated; however, clinicians should be aware of the possibility of dose-independent drug-induced cutaneous toxicity with this medication. This report reviews the mechanism and use of eltrombopag along with a summary of associated adverse cutaneous reactions. PMID- 27617609 TI - Narrowband UVB-induced iatrogenic polymorphous light eruption: a case and suggestions to overcome this rare complication. AB - Polymorphous light eruption (PMLE) is the most common photodermatosis characterized by pruritic papules and papulovesicles, which appear hours to days following ultraviolet (UV) exposure. Herein, the authors report successful treatment of generalized plaque psoriasis with Goeckerman regimen in a patient despite new onset iatrogenic PMLE following narrowband (NB) UVB therapy. Although further studies are necessary, this case suggests that the co-existence of psoriasis and PMLE should not prevent the use of phototherapy; phototherapy, especially as part of the Goeckerman regimen, remains a valuable treatment option for psoriasis in patients with PMLE. PMID- 27617610 TI - Unusual manifestation of mucosal plasmacytosis mimicking erythema multiforme. AB - Mucosal plasmacytoses constitute a group of idiopathic inflammatory disorders, characterized by a dense infiltrate of plasma cells at the mucocutaneous junction without any recognizable dermatosis or neoplasm. We report an unusual clinical presentation of mucosal plasmacytosis presenting with hemorrhagic crusting of the lips, mimicking erythema multiforme. PMID- 27617611 TI - A Violaceous Nodule in a Lung-transplant Patient. AB - Posttransplantation lymphoproliferative disorder (PTLD) is a rare complication of solid organ or allogenic bone marrow transplantation. Cases localized to the skin are even rarer, with only around 100 cases recorded in the literature [2]. We present a case of 60 year-old-woman, a lung transplant recipient, who presented with an asymptomatic violaceous nodule on her left medial calf. Histopathology was consistent with PTLD of the B-cell subtype, EBV negative. This case is unique in that it was of the B cell subtype of cutaneous PTLD, which has been less commonly observed than the T cell subtype. In addition, the case was EBV negative, which is rare in B cell cutaneous PTLD. The patient was treated with rituximab 600 mg IV weekly for four weeks and cytomegalovirus immune globulin (Cytogam) 100 mg/kg once, with resolution of the nodule. PMID- 27617612 TI - Motivating medical students by utilizing dermatology-oriented online quizzes. AB - BACKGROUND: Online quiz competitions can facilitate extra-classroom interactions between faculty and medical students. Owing to decreased class attendance nationwide, teaching faculty might revamp their approach to medical education by providing online resources and methods for communication. OBJECTIVE: To explore if the use of online quizzes and social media can result in improved interactions between faculty and students. METHODS: A pilot study conducted from April 7th, 2015 to June 11th, 2015 at Northeast Ohio Medical University (NEOMED) among participants from the second year medical school class. Ten one-question quizzes created using Google Forms were announced over Twitter and email at the rate of one quiz per week. The first correct responder of each quiz chose a five-dollar coffee shop gift card, movie ticket, or a meeting with a NEOMED faculty person as their prize. RESULTS: An average of 23.8% of the second year medical student class at NEOMED participated per quiz. A total of 80 individuals (55.9%) submitted 340 responses during the competition. LIMITATIONS: This is a single center study with a limited sample size. CONCLUSIONS AND RELEVANCE: This study presents a process evaluation for the use of online quiz competitions amongst medical students. Optional online quizzes with small incentives may foster motivational competition among medical students, increase online interactions with faculty, and serve as study material for exams. PMID- 27617613 TI - Lymphangitis occurring after intralesional Candida antigen injection for verruca vulgaris. AB - Verruca vulgaris is a common dermatological disease with many treatment options including destructive modalities and more recently, immunotherapy. Intralesional injections of Candida antigen have been described as a safe and effective treatment with the most common adverse reactions including local reactions (burning, blistering, peeling), local erythema, and pain at the injection site. We describe the first reported case of lymphangitis after intralesional Candida antigen injection for verruca vulgaris in a healthy 18-year-old woman. The lymphangitis rapidly resolved with ibuprofen and cold compresses. Physicians should be aware of this potential adverse reaction when using this treatment modality and should be familiar with appropriate treatment of subsequent lymphangitis. PMID- 27617614 TI - Non-invasive methods to establish the diagnosis of terra firma-forme dermatosis: The SMART (Skin Modified by Alcohol Rubbing Test) evaluation and dermoscopy. AB - Terra firma-forme dermatosis may mimic a variety of hyper pigmented dermatoses. The diagnosis can be characterized using dermoscopy and confirmed with the SMART (Skin Modified by Alcohol Rubbing Test) evaluation. When terra firma-forme dermatosis (Duncan's dirty dermatosis) is clinically suspected, clearance of the dermatosis follows rubbing the affected skin with 70% isopropyl alcohol. PMID- 27617615 TI - Effective local anesthesia for onabotulinumtoxin A injections to treat hyperhidrosis associated with traumatic amputation. AB - BACKGROUND: Botulinum toxin type A (BTX-A) injections are an effective treatment for controlling hyperhidrosis at sites of amputation. Hyperesthesia associated with amputated limbs is a major barrier to performing this procedure under local anesthesia. OBJECTIVE: To present a novel method for improving local anesthesia with BTX-A injections. Methods & RESULTS: A 29-year-old military veteran with a below-the-knee amputation of his right leg was suffering from amputation site hyperhidrosis, which was impeding his ability to comfortably wear a prosthesis. Prior to presenting to our clinic, the patient received one treatment of BTX-A injections to his amputation stump while under general anesthesia for surgical repair of trauma-related injuries. In our dermatology clinic, we repeated the procedure using topical lidocaine-prilocaine (30 gm total) for local anesthesia. This provided effective relief of hyperhidrosis for 6 months, but the procedure was very painful (9/10 intensity). We repeated the same procedure 6 months later, using ice in addition to topical lidocaine-prilocaine (30 gm) for local anesthesia; this resulted in reduced pain (3/10 intensity) for the patient. CONCLUSIONS: We suggest using ice in combination with a topical anesthetic as an effective method for pain control that avoids general anesthesia in treating amputation-associated hyperhidrosis. PMID- 27617616 TI - Lesoes vesiculares e prurido intenso em paciente com sifilis secundaria:manifestacao clinica atipica. AB - Syphilis is an infectious disease with mucocutaneous lesions that are characteristic of their stage (primary, secondary, or tertiary). These are not always typical and may have other morphologies and unusual symptoms, making diagnosis difficult. The report herein is of a healthy woman with vesicular lesions associated with intense itching. The diagnosis of secondary syphilis was confirmed with VDRL 1/512 and FTA Abs positive. Histopathology showed spongiosis in the epidermis and infiltrated lymphocytes and plasma cell in the dermis. Clinical improvement occurred after the first dose of benzathine penicillin. In the literature, few cases of vesicular lesions in syphilis have been found and itching is mentioned as uncharacteristic . Histology showing spongiosis is also unusual. PMID- 27617617 TI - There's no place like home: an analysis of migration patterns of dermatology residents prior to, during, and after their training. AB - Previous studies have established migration patterns between the geographic location of physicians' residency programs and their first post-training job. Our study explores the patterns of migration of pre-residency education locations with residency and post-residency geography. We analyzed responses to an annual survey administered between 2008 and 2013 to participants of the board examination review courses organized by Galderma Laboratories. Geography of high school (HS), medical school (MS), residency, and first job location were highly correlated. The Midwest and South retained the most residents from HS (70% each), whereas the West retained the lowest percent of residents from HS (33%). The West and Northeast exported about half of their HS graduates to the South and MW for residency. The South retained the largest proportion of its trainees post residency (75%). Our data revealed that both HS and MS locations are closely related to residents' ultimate employment locations. This information may be useful to training program directors and chairpersons as they manage recruitment and retention of trainees and faculty and may inform plans to address geographic workforce imbalances. PMID- 27617618 TI - Dominant Versus Nondominant Hand Cardiopulmonary Resuscitation: Is There Really True Dominance? PMID- 27617619 TI - Acute Gene Expression Profile of Lung Tissue Following Sulfur Mustard Inhalation Exposure in Large Anesthetized Swine. AB - Sulfur mustard (HD) is a vesicating and alkylating agent widely used on the battlefield during World War I and more recently in the Iran-Iraq War. It targets the eyes, skin, and lungs, producing skin burns, conjunctivitis, and compromised respiratory function; early acute effects lead to long-term consequences. However, it is the effects on the lungs that drive morbidity and eventual mortality. The temporal postexposure response to HD within lung tissue raises the question of whether toxicity is driven by the alkylating properties of HD on critical homeostatic pathways. We have established an anesthetized swine model of inhaled HD vapor exposure to investigate the toxic effects of HD 12 h postexposure. Large white female swine were anesthetized and instrumented prior to exposure to air, 60 (sublethal) or 100 MUg.kg-1 (~LD40) doses of HD (10 min). Physiological parameters were continuously assessed. Data indicate that exposure to 100 MUg.kg-1 HD lowered arterial blood oxygenation and increased shunt fraction and lavage protein compared with those of air-exposed controls and the 60 MUg.kg-1 dose of HD. Histopathology showed an increased total pathology score between the 100 MUg.kg-1 HD group and air-exposed controls. Principal component analysis of differentially expressed genes demonstrated a distinct and separable response of inhaled HD between air-exposed controls and the 60 and 100 MUg.kg-1 doses of HD. Canonical pathway analysis demonstrated changes in acute phase response signaling, aryl hydrocarbon receptor signaling, NRF-2 mediated oxidative stress, and zymosterol biosynthesis in the 60 and 100 MUg.kg-1 HD dose group. Transcriptional changes also indicated alterations in immune response, cancer, and cell signaling and metabolism canonical pathways. The 100 MUg.kg-1 dose group also showed significant changes in cholesterol biosynthesis. Taken together, exposure to inhaled HD had a significant effect on physiological responses coinciding with acute changes in gene expression and lung histopathology. In addition, transcriptomics support the observed beneficial effects of N-acetyl-l cysteine for treatment of acute inhalation HD exposure. PMID- 27617620 TI - The Influence of Pay-To-Play Fees on Participation in Interscholastic Sports: A School-Level Analysis of Michigan's Public Schools. AB - BACKGROUND: School districts in the United States are turning toward new sources of revenue to maintain their interscholastic sports programs. One common revenue generating policy is the implementation of participation fees, also known as pay to-play. One concern of the growing trend of participation fees is how it impacts student participation opportunities. This study looks at how pay-to-play fees are impacting participation opportunities and participation rates in the state of Michigan. METHODS: Through merging 3 school-level data sets, Civil Rights Data Collection, the Common Core of Data, and participation information from MHSAA (Michigan High School Athletic Association), bivariate analysis and ordinary least squares regression were used in our analysis. RESULTS: Our findings indicate that certain types of schools are able to support pay-to-play fees: relatively large schools that are located in suburban, white communities, with relatively low poverty rates. We also found that participation fees are not decreasing the number of sport opportunities for students, participation opportunities are higher in schools with fees; but participation rates are similar between schools with and without participation fees. CONCLUSIONS: Participation fee policy implications are discussed and we offer suggestions for future research. PMID- 27617621 TI - Immobilized Biocatalyst for Detection and Destruction of the Insensitive Explosive, 2,4-Dinitroanisole (DNAN). AB - Accurate and convenient detection of explosive components is vital for a wide spectrum of applications ranging from national security and demilitarization to environmental monitoring and restoration. With the increasing use of DNAN as a replacement for 2,4,6-trinitrotoluene (TNT) in insensitive explosive formulations, there has been a growing interest in strategies to minimize its release and to understand and predict its behavior in the environment. Consequently, a convenient tool for its detection and destruction could enable development of more effective decontamination and demilitarization strategies. Biosensors and biocatalysts have limited applicability to the more traditional explosives because of the inherent limitations of the relevant enzymes. Here, we report a highly specific, convenient and robust biocatalyst based on a novel ether hydrolase enzyme, DNAN demethylase (that requires no cofactors), from a Nocardioides strain that can mineralize DNAN. Biogenic silica encapsulation was used to stabilize the enzyme and enable it to be packed into a model microcolumn for application as a biosensor or as a bioreactor for continuous destruction of DNAN. The immobilized enzyme was stable and not inhibited by other insensitive munitions constituents. An alternative method for DNAN detection involved coating the encapsulated enzyme on cellulose filter paper. The hydrolase based biocatalyst could provide the basis for a wide spectrum of applications including detection, identification, destruction or inertion of explosives containing DNAN (demilitarization operations), and for environmental restorations. PMID- 27617622 TI - Clinical Characteristics of Voice, Speech, and Swallowing Disorders in Oromandibular Dystonia. AB - Purpose: To better define the clinical characteristics of idiopathic oromandibular dystonia, we studied voice, speech, and swallowing disorders and their impact on activities of daily living. Method: Fourteen consecutive patients with idiopathic oromandibular dystonia and 14 matched, healthy control subjects were included in the study. Results: Dysarthria was the most common disorder and its characteristics varied from one patient to another. However, we frequently observed a hyperkinetic, dysarthric profile characterized by imprecise consonants, a rough voice, changes in intensity, and hypernasality. Dysphagia appeared to be slightly less frequent and less disabling than dysarthria. Most patients had difficulty swallowing solids, and the oral phase was particularly problematic. Dysarthria and dysphagia affected activities of daily living in general and the psychological/emotional domain in particular. Conclusions: The characteristics of dysarthria in oromandibular dystonia vary significantly from one patient to another due to differences in the set of affected muscles, so each patient should receive a personalized rehabilitation program. Dysarthria was the most prominent symptom, although spasmodic dysphonia was more frequent than expected. Further laboratory-based studies are needed to clarify the mechanisms and consequences of dysphagia in oromandibular dystonia. PMID- 27617623 TI - Generation of Hydrogen from Water: A Pd-Catalyzed Reduction of Water Using Diboron Reagent at Ambient Conditions. AB - Production of hydrogen from renewable sources, particularly from water, is an intensive area of research, which has far-reaching relevance in hydrogen economy. A homogeneous catalytic method is presented for producing clean hydrogen gas from water, in a reaction of water with a diboron compound as the reductant, under ambient reaction conditions. The Pd-catalytic system is stable in water and displays excellent recyclability. Hydroxy analogues such as alcohols are compatible with the Pd/B2Pin2 system and generate hydrogen gas efficiently. The B2Pin2-H2O system, in the presence of palladium, is an excellent catalytic system for selective hydrogenation of olefins. PMID- 27617624 TI - Synthesis of Unsymmetrical Diaryl Acetamides, Benzofurans, Benzophenones, and Xanthenes by Transition-Metal-Free Oxidative Cross-Coupling of sp3 and sp2 C-H Bonds. AB - A chemo- and regioselective intermolecular sp3 C-H and sp2 C-H coupling reaction for C-C bond formation is described to access unsymmetrical diaryl acetamides under TM-free conditions from sec- and tert-arylacetamides and nitroarenes using tert-butoxide base in DMSO at room temperature. The coupling partners with sensitive functionalities such as chloro, bromo, hydroxy, and cyano were also amenable to the developed reaction. Synthesized alpha-(2/4-nitroaryl) phenylacetamides have been transformed into biologically important benzofurans, xanthenes, diaryl indoles, and unsymmetrical benzophenones by novel routes without applying a transition metal. Overall, an economical, yet efficient, strategy has been devised to access unsymmetrical diarylacetamides with the possibility of their further elaboration into a variety of biologically important heterocycles. Mechanistic understanding suggests that the reaction proceeds by a nucleophilic addition of a phenylacetamide carbanion, which is generated in the presence of tert-butoxide base, to the para or ortho (if para is substituted) position of nitrobenzene. The formed alpha-(4-nitrocyclohexa-2,4-dien-1-yl) phenylacetamide anion intermediate oxidized by a basic solution of DMSO or atmospheric oxygen led to the desired sp3 C-H and sp2 C-H coupled alpha-(2/4 nitroaryl) phenylacetamides. PMID- 27617625 TI - Similar Running Economy With Different Running Patterns Along the Aerial Terrestrial Continuum. AB - PURPOSE: No unique or ideal running pattern is the most economical for all runners. Classifying the global running patterns of individuals into 2 categories (aerial and terrestrial) using the Volodalen method could permit a better understanding of the relationship between running economy (RE) and biomechanics. The main purpose was to compare the RE of aerial and terrestrial runners. METHODS: Two coaches classified 58 runners into aerial (n = 29) or terrestrial (n = 29) running patterns on the basis of visual observations. RE, muscle activity, kinematics, and spatiotemporal parameters of both groups were measured during a 5 min run at 12 km/h on a treadmill. Maximal oxygen uptake (VO2max) and peak treadmill speed (PTS) were assessed during an incremental running test. RESULTS: No differences were observed between aerial and terrestrial patterns for RE, VO2max, and PTS. However, at 12 km/h, aerial runners exhibited earlier gastrocnemius lateralis activation in preparation for contact, less dorsiflexion at ground contact, higher coactivation indexes, and greater leg stiffness during stance phase than terrestrial runners. Terrestrial runners had more pronounced semitendinosus activation at the start and end of the running cycle, shorter flight time, greater leg compression, and a more rear-foot strike. CONCLUSIONS: Different running patterns were associated with similar RE. Aerial runners appear to rely more on elastic energy utilization with a rapid eccentric-concentric coupling time, whereas terrestrial runners appear to propel the body more forward rather than upward to limit work against gravity. Excluding runners with a mixed running pattern from analyses did not affect study interpretation. PMID- 27617626 TI - Current status and diagnostic values of the Bethesda system for reporting thyroid cytopathology in a papillary thyroid carcinoma-prevalent area. AB - BACKGROUND: Most studies validating the Bethesda system for reporting thyroid cytopathology (TBSRTC) have been conducted in Western countries. We explored the current status of TBSRTC in an area where most thyroid malignancies are papillary carcinomas. METHODS: Fine-needle aspirations (FNAs) of thyroid nodules performed in 2013 were retrospectively analyzed and the results were compared to final pathology on resection. RESULTS: Of 1947 FNAs, 1925 (98.9%) were reported using TBSRTC. Among 381 resected lesions, 27.3% of nondiagnostic, 19.6% of benign, 56.0% of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), 33.3% of follicular neoplasm/suspicious for a follicular neoplasm (FN/SFN), 97.7% of suspicious for malignancy, and 100.0% of malignant lesions were malignant on pathology. The sensitivity and specificity of FNA using TBSRTC were 96.7% and 84.1%, respectively. CONCLUSION: TBSRTC works well in an area in which papillary thyroid cancer is prevalent; however, it may underestimate malignancy rates in AUS/FLUS, benign, and nondiagnostic categories. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: 269-274, 2017. PMID- 27617627 TI - Competitive Development in Pharmacologic Classes: Market Entry and the Timing of Development. AB - We examined data on the entry rates of second and later entrants in 43 pharmacologic classes, as well as the timing of patent filings and development milestones for 79 later-in-class drugs. The median time to when a second entrant was approved was 2.7 years. A substantial majority of later-in-class drugs had a patent filed and were in clinical development prior to the approval of the first in-class drug. PMID- 27617628 TI - Development of Lymphatic Capillary Network Along the Alveolar Walls of Autopsied Human Lungs with Pneumonia. AB - BACKGROUND: Limited information is available regarding the lymphatic vasculature during pneumonia. OBJECTIVE: To characterize lymphatic vasculatures in autopsied cadavers with pneumonia. METHODS: Paraffin-embedded lung tissues obtained from 20 autopsied cadavers with complicated pneumonia and 10 control cadavers without pneumonia were used for immunohistochemical analyses using primary antibodies against podoplanin, vascular endothelial growth factor receptor-3 (VEGFR-3), CD34, vascular endothelial growth factor (VEGF)-C, VEGF-D, CD73, and CD163. RESULTS: There was no difference in the vascular density of podoplanin+ usual lymphatics between the individuals with and without pneumonia. In half of the cadavers with pneumonia, however, a network of podoplanin+ cells lying together in a side-by-side bead-like arrangement appeared along the alveolar septa; however, this was absent in the control cadavers. The podoplanin+ cells in the network were characterized by a weaker expression of podoplanin, relative to usual lymphatics, and the occasional presence of ductal structures. Although podoplanin+ cells were not coexpressed with VEGFR-3, a part of the network was connected to CD73+ afferent lymphatics. The network showed an intertwined relationship with CD34+ capillaries, suggesting that the network represents lymphatic capillaries. The number of CD163+ macrophages was significantly increased in individuals with the network than those without the network, while a significant decrease in neutrophils was observed. VEGF-C expressed in CD163+ macrophages and type II epithelial cells was observed in the cadavers with the network. CONCLUSION: The development of lymphatic capillary networks along the alveolar septa rather than the usual lymphangiogenesis was noted in autopsied individuals with pneumonia. PMID- 27617629 TI - Lifelong Gender Gap in Risk of Incident Myocardial Infarction: The Tromso Study. AB - Importance: It is not clear to what extent the higher incidence of coronary heart disease (CHD) in men vs women is explained by differences in risk factor levels because few studies have presented adjusted risk estimates for sex. Moreover, the increase in risk of CHD in postmenopausal women, possibly hormone related, may eventually eliminate the sex contrast in risk, but age-specific risk estimates are scarce. Objective: To quantify the difference in risk of incident myocardial infarction (MI) between men and women. Design, Setting and Participants: Population-based prospective study from Tromso, Norway, comprising 33 997 individuals (51% women). Median follow-up time during ages 35 to 102 years was 17.6 years. Incidence rates (IRs) and incidence rate ratios (IRRs, relative risk) of MI were calculated in Poisson regression analysis of person-years at risk. The data analysis was performed in November 2015. Exposures: Sex, age, birth cohort, serum lipid levels, blood pressure, lifestyle factors, diabetes. Main Outcomes and Measures: Incident MI. Results: A total of 2793 individuals (886 women) received a diagnosis of MI during follow-up in the period 1979 through 2012. The IR increased with age in both sexes, with lower rates for women until age 95 years. Adjusted for age and birth cohort, the overall IRR for men vs women was 2.72 (95% CI, 2.50-2.96). Adjustment for high-density lipoprotein cholesterol and total cholesterol levels had the strongest impact on the risk estimate for sex, followed by diastolic blood pressure and smoking. However, the sex difference remained substantial even after adjustment for these factors (IRR, 2.07; 95% CI, 1.89-2.26). Men had higher risk throughout life, but the IRRs decreased with age (3.64 [95% CI, 2.85-4.65], 2.00 [95% CI, 1.76-2.28], and 1.66 [95% CI, 1.42-1.95] for age groups 35-54, 55-74, and 75-94 years, respectively). Adjustment for systolic blood pressure, diabetes, body mass index, and physical activity had no notable impact. Conclusions and Relevance: The observed sex contrast in risk of MI cannot be explained by differences in established CHD risk factors. The gender gap persisted throughout life but declined with age as a result of a more pronounced flattening of risk level changes in middle-aged men. The minor changes in IRs when moving from premenopausal to postmenopausal age in women make it unlikely that changes in female hormone levels influence the risk of MI. PMID- 27617631 TI - Stereocontrolled Total Synthesis of Muraymycin D1 Having a Dual Mode of Action against Mycobacterium tuberculosis. AB - A stereocontrolled first total synthesis of muraymycin D1 (1) has been achieved. The synthetic route is highly stereoselective, featuring (1) selective beta ribosylation of the C2-methylated amino ribose, (2) selective Strecker reaction, and (3) ring-opening reaction of a diastereomeric mixture of a diaminolactone to synthesize muraymycidine (epi-capreomycidine). The acid-cleavable protecting groups for secondary alcohol and uridine ureido nitrogen are applied for simultaneous deprotections with the Boc and tBu groups. Muraymycin D1 (1) and its amide derivatives (2 and 3) exhibited growth inhibitory activity against Mycobacterium tuberculosis (MIC50 = 1.56-6.25 MUg/mL) and strong enzyme inhibitory activities against the bacterial phosphotransferases (MurX and WecA) (IC50 = 0.096-0.69 MUM). PMID- 27617633 TI - Toward Dendrite-Free Lithium Deposition via Structural and Interfacial Synergistic Effects of 3D Graphene@Ni Scaffold. AB - Owing to its ultrahigh specific capacity and low electrochemical potential, lithium (Li) metal is regarded as one of the most attractive anode materials for next-generation lithium batteries. Nevertheless, the commercialization of Li metal-based rechargeable batteries (LiMBs) has been retarded by the uncontrollable growth of Li dendrites, as well as the resulting poor cycle stability and safety hazards. In this work, a 3D graphene@Ni scaffold has been proposed to accomplish dendrite-free Li deposition via structural and interfacial synergistic effects. Due to the intrinsic high surface area used to reduce the effective electrode current density and the surface-coated graphene working as an artificial protection layer to provide high cycle stability as well as suppress the growth of Li dendrites, the Coulombic efficiencies of Li deposition on 3D graphene@Ni foam after 100 cycles can be sustained as high as 96, 98, and 92% at the current densities of 0.25, 0.5, and 1.0 mA cm-2, respectively, which shows more excellent cycle stability than that of its planar Cu foil and bare Ni foam counterparts. The results obtained here demonstrate that the comprehensive consideration of multiaspect factors could be more help to enhance the performance of Li metal anode so as to achieve its real application in next generation LiMBs. PMID- 27617635 TI - Potassium isotopic evidence for a high-energy giant impact origin of the Moon. AB - The Earth-Moon system has unique chemical and isotopic signatures compared with other planetary bodies; any successful model for the origin of this system therefore has to satisfy these chemical and isotopic constraints. The Moon is substantially depleted in volatile elements such as potassium compared with the Earth and the bulk solar composition, and it has long been thought to be the result of a catastrophic Moon-forming giant impact event. Volatile-element depleted bodies such as the Moon were expected to be enriched in heavy potassium isotopes during the loss of volatiles; however such enrichment was never found. Here we report new high-precision potassium isotope data for the Earth, the Moon and chondritic meteorites. We found that the lunar rocks are significantly (>2sigma) enriched in the heavy isotopes of potassium compared to the Earth and chondrites (by around 0.4 parts per thousand). The enrichment of the heavy isotope of potassium in lunar rocks compared with those of the Earth and chondrites can be best explained as the result of the incomplete condensation of a bulk silicate Earth vapour at an ambient pressure that is higher than 10 bar. We used these coupled constraints of the chemical loss and isotopic fractionation of K to compare two recent dynamic models that were used to explain the identical non-mass-dependent isotope composition of the Earth and the Moon. Our K isotope result is inconsistent with the low-energy disk equilibration model, but supports the high-energy, high-angular-momentum giant impact model for the origin of the Moon. High-precision potassium isotope data can also be used as a 'palaeo barometer' to reveal the physical conditions during the Moon-forming event. PMID- 27617636 TI - Neurocognitive predictors of posttraumatic stress disorder symptoms in children 6 months after traumatic brain injury: A prospective study. AB - OBJECTIVE: Various neurocognitive mechanisms have been proposed to explain the development of Posttraumatic Stress Disorder (PTSD) symptoms. However, the neurocognitive mechanisms underlying comorbid PTSD following Traumatic Brain Injury (TBI) have not been fully investigated, especially among children. This study prospectively examined the influence of theorized neurocognitive deficits at 3 months post pediatric TBI on the development of PTSD symptoms 6 months postinjury. METHOD: One hundred sixty-six children aged between 6 and 14 years were recruited after sustaining a TBI. Their demographic information and injury severity were assessed at 2 months postinjury, their neurocognitive outcomes in selective attention, sustained attention, verbal learning, working memory, and processing speed were assessed at 3 months postinjury, and PTSD symptoms were measured at 6 months postinjury. RESULTS: Consistent with the Neurobiological Theory of PTSD, sustained attention deficits 3 months postinjury emerged as the key predictor for greater future PTSD severity at 6 months, especially following a mild TBI. However, contrary to the expectations of the Emotional Processing Theory and Dual Representation Theory, verbal learning and working memory deficits at 3 months postinjury protected children from the development of PTSD symptoms 6 months postinjury. CONCLUSIONS: PTSD involves a complex interplay between attention and memory functions post pediatric TBI. When trauma memory is relatively intact, difficulties disengaging from distractors contribute to the development of PTSD symptoms. (PsycINFO Database Record PMID- 27617634 TI - Prefrontal Cortex-Mediated Impairments in a Genetic Model of NMDA Receptor Hypofunction Are Reversed by the Novel M1 PAM VU6004256. AB - Abnormalities in the signaling of the N-methyl-d-aspartate subtype of the glutamate receptor (NMDAR) within cortical and limbic brain regions are thought to underlie many of the complex cognitive and affective symptoms observed in individuals with schizophrenia. The M1 muscarinic acetylcholine receptor (mAChR) subtype is a closely coupled signaling partner of the NMDAR. Accumulating evidence suggests that development of selective positive allosteric modulators (PAMs) of the M1 receptor represent an important treatment strategy for the potential normalization of disruptions in NMDAR signaling in patients with schizophrenia. In the present studies, we evaluated the effects of the novel and highly potent M1 PAM, VU6004256, in ameliorating selective prefrontal cortical (PFC)-mediated physiologic and cognitive abnormalities in a genetic mouse model of global reduction in the NR1 subunit of the NMDAR (NR1 knockdown [KD]). Using slice-based extracellular field potential recordings, deficits in muscarinic agonist-induced long-term depression (LTD) in layer V of the PFC in the NR1 KD mice were normalized with bath application of VU6004256. Systemic administration of VU6004256 also reduced excessive pyramidal neuron firing in layer V PFC neurons in awake, freely moving NR1 KD mice. Moreover, selective potentiation of M1 by VU6004256 reversed the performance impairments of NR1 KD mice observed in two preclinical models of PFC-mediated learning, specifically the novel object recognition and cue-mediated fear conditioning tasks. VU6004256 also produced a robust, dose-dependent reduction in the hyperlocomotor activity of NR1 KD mice. Taken together, the current findings provide further support for M1 PAMs as a novel therapeutic approach for the PFC-mediated impairments in schizophrenia. PMID- 27617639 TI - Phenotypes of Dravet Syndrome. AB - Researchers from the University of Washington in Seattle studied selective heterozygous and homozygous deletions of the voltage gated sodium channel (Nav1.1) in parvalbumin (PV) or somato-statin (SST) expressing interneurons. PMID- 27617637 TI - Engagement with the auditory processing system during targeted auditory cognitive training mediates changes in cognitive outcomes in individuals with schizophrenia. AB - BACKGROUND: Individuals with schizophrenia who engage in targeted cognitive training (TCT) of the auditory system show generalized cognitive improvements. The high degree of variability in cognitive gains maybe due to individual differences in the level of engagement of the underlying neural system target. METHOD: 131 individuals with schizophrenia underwent 40 hours of TCT. We identified target engagement of auditory system processing efficiency by modeling subject-specific trajectories of auditory processing speed (APS) over time. Lowess analysis, mixed models repeated measures analysis, and latent growth curve modeling were used to examine whether APS trajectories were moderated by age and illness duration, and mediated improvements in cognitive outcome measures. RESULTS: We observed significant improvements in APS from baseline to 20 hours of training (initial change), followed by a flat APS trajectory (plateau) at subsequent time-points. Participants showed interindividual variability in the steepness of the initial APS change and in the APS plateau achieved and sustained between 20 and 40 hours. We found that participants who achieved the fastest APS plateau, showed the greatest transfer effects to untrained cognitive domains. CONCLUSIONS: There is a significant association between an individual's ability to generate and sustain auditory processing efficiency and their degree of cognitive improvement after TCT, independent of baseline neurocognition. APS plateau may therefore represent a behavioral measure of target engagement mediating treatment response. Future studies should examine the optimal plateau of auditory processing efficiency required to induce significant cognitive improvements, in the context of interindividual differences in neural plasticity and sensory system efficiency that characterize schizophrenia. (PsycINFO Database Record PMID- 27617640 TI - Dichroism in Helicoidal Crystals. AB - Accounting for the interactions of light with heterogeneous, anisotropic, absorbing, optically active media is part of the characterization of complex, transparent materials. Stained biological structures in thin tissue sections share many of these features, but systematic optical analyses beyond the employ of the simple petrographic microscopes have not be established. Here, this accounting is made for polycrystalline, spherulitic bundles of twisted d-mannitol lamellae grown from melts containing light-absorbing molecules. It has long been known that a significant percentage of molecular crystals readily grow as helicoidal ribbons with mesoscale pitches, but a general appreciation of the commonality of these non-classical crystal forms has been lost. Helicoidal crystal twisting was typically assayed by analyzing refractivity modulation in the petrographic microscope. However, by growing twisted crystals from melts in the presence of dissolved, light-absorbing molecules, crystal twisting can be assayed by analyzing the dichroism, both linear and circular. The term "helicoidal dichroism" is used here to describe the optical consequences of anisotropic absorbers precessing around radii of twisted crystalline fibrils or lamellae. d-Mannitol twists in two polymorphic forms, alpha and delta. The two polymorphs, when grown from supercooled melts in the presence of a variety of histochemical stains and textile dyes, are strongly dichroic in linearly polarized white light. The bis-azo dye Chicago sky blue is modeled because it is most absorbing when parallel and perpendicular to the radial axes in the respective spherulitic polymorphs. Optical properties were measured using Mueller matrix imaging polarimetry and simulated by taking into account the microstructure of the lamellae. The optical analysis of the dyed, patterned polycrystals clarifies aspects of the mesostructure that can be difficult to extract from bundles of tightly packed fibrils. PMID- 27617641 TI - Simulation for Percutaneous Renal Access: Where Are We? AB - OBJECTIVES: Percutaneous renal access (PCA) is a challenging step during percutaneous nephrolithotomy. The aim of this study is to review the literature for different types of simulators described for PCA. METHODS: Databases of Medline, Embase, Cochrane Library, OvidSP, and Google Scholar were systematically searched until May 2016. The studies were analyzed regarding the type of simulator (nonbiologic, biologic, live animal, and virtual reality [VR]), type of validity (face, content, construct, and predictive), cost-effectiveness, and whether these simulators have been used for training and/or assessment of PCA. In addition, the study looked at the educational impact of these simulators in terms of the transfer of PCA skills to the operating room. RESULTS: Several bench, animal, and VR simulators for training in PCA were identified. Only few studies were found on assessment of PCA skills. Biological bench models used porcine or bovine kidneys wrapped within foam, silicone, chicken carcass, or full-thickness skin flap alone. Other biological models used additional subcutaneous fascia, muscle, or ribs. Nonbiological models used prototypes, including 3D printing. Only one study reported the use of anesthetized live pig for training. The PERC MentorTM was the only VR simulator, which has been validated for training and assessment of PCA skills. However, none of these studies assessed the educational impact of PCA simulators. Furthermore, most of the studies did not address the validity and the cost of the simulator. CONCLUSIONS: While several biological and nonbiological PCA models exist, there is paucity of literature regarding the validity and educational impact of these simulators. The PERC Mentor simulator is the sole validated simulator for training and assessment of PCA skills. However, it is expensive and there is little evidence of its educational impact. Therefore, more research is needed to validate the available simulators and assess their educational impact for urology trainees. PMID- 27617642 TI - The Rho guanine nucleotide exchange factor ARHGEF5 promotes tumor malignancy via epithelial-mesenchymal transition. AB - Epithelial tumor cells often acquire malignant properties, such as invasion/metastasis and uncontrolled cell growth, by undergoing epithelial mesenchymal transition (EMT). However, the mechanisms by which EMT contributes to malignant progression remain elusive. Here we show that the Rho guanine nucleotide exchange factor (GEF) ARHGEF5 promotes tumor malignancy in a manner dependent on EMT status. We previously identified ARHGEF5, a member of the Dbl family of GEFs, as a multifunctional mediator of Src-induced cell invasion and tumor growth. In the present study, ARHGEF5 was upregulated during tumor growth factor-beta-induced EMT in human epithelial MCF10A cells, and promoted cell migration by activating the Rho-ROCK pathway. ARHGEF5 was necessary for the invasive and in vivo metastatic activity of human colorectal cancer HCT116 cells. These findings underscore the crucial role of ARHGEF5 in cell migration and invasion/metastasis. An in vivo tumorigenesis assay revealed that ARHGEF5 had the potential to promote tumor growth via the phosphatidylinositol 3-kinase (PI3K) pathway. However, ARHGEF5 was not required for tumor growth in epithelial-like human colorectal cancer HCT116 and HT29 cells, whereas the growth of mesenchymal like SW480 and SW620 cells depended on ARHGEF5. Induction of EMT by tumor necrosis factor-alpha or Slug in HCT116 cells resulted in the dependence of tumor growth on ARHGEF5. In these mesenchymal-like cells, Akt was activated via ARHGEF5 and its activity was required for tumor growth. Analysis of a transcriptome data set revealed that the combination of ARHGEF5 upregulation and E-cadherin downregulation or Snail upregulation was significantly correlated with poor prognosis in patients with colorectal cancers. Taken together, our findings suggest that EMT-induced ARHGEF5 activation contributes to the progression of tumor malignancy. ARHGEF5 may serve as a potential therapeutic target in a subset of malignant tumors that have undergone EMT. PMID- 27617643 TI - ZEB1 induces EPB41L5 in the cancer mesenchymal program that drives ARF6-based invasion, metastasis and drug resistance. AB - Onset of the cancer mesenchymal program is closely associated with cancer malignancy and drug resistance. Among the different epithelial-mesenchymal transition (EMT)-associated transcriptional factors, ZEB1 has a key role in inducing the mesenchymal phenotypes and stem cell-like properties of different breast cancer cells. ARF6 and its effector AMAP1 are frequently overexpressed in breast cancer cells, and promote invasion, metastasis and drug resistance. EPB41L5 is induced during EMT, and mediates the disruption of E-cadherin-based cell-cell adhesion and the promotion of focal adhesion dynamics. Here we show that EPB41L5 is an integral component of the ARF6-based pathway, which is induced by ZEB1. We found that EPB41L5 is expressed at high levels in malignant breast cancer cells and binds to AMAP1. ZEB1 induced EPB41L5 both in cancer cells and normal cells. This relationship was recaptured with The Cancer Genome Atlas RNASeq data set, and correlated with the poor outcome of the patients. In contrast, diversified events, such as tumor growth factor beta1 stimulation, expression of SNAI1 and TP53 mutation, can each cause the induction of ZEB1 and EPB41L5, depending on the cellular context. Our results demonstrated that the ZEB1-EPB41L5 axis is at the core of the cancer mesenchymal program that drives ARF6-based invasion, metastasis and drug resistance of significant populations of primary breast cancers, and is tightly correlated with the poor outcomes of patients. PMID- 27617645 TI - [Not Available]. PMID- 27617644 TI - Interleukin-27 Inhibits Herpes Simplex Virus Type 1 Infection by Activating STAT1 and 3, Interleukin-6, and Chemokines IP-10 and MIG. AB - Interleukin-27 (IL-27) inhibits the replication of many viruses, but the mechanism differs according to virus and cell type. In this study, we observed that IL-27 expression was upregulated in herpes simplex virus type 1 (HSV-1) infected SJL/J mice, which led us to further investigate the role of IL-27 in HSV 1 infection using epithelial, glioma, and immunological cells as cell models. We showed that in all studied cell lines, the IL-27 messenger RNA (mRNA) level was upregulated due to the HSV-1 infection. When the cells were primed with IL-27 before the virus infection, the virus release was prevented, indicating an antiviral role of IL-27 in HSV-1 infection. Furthermore, we observed that IL-27 secretion to the culture medium was reduced in infected epithelial and immunological cells, but not in glioma cells. Not surprisingly, HSV-1 induced type I, II, and III interferons regardless of cell line, but IL-27 itself caused varying interferon responses dependent on cell type. However, common to all cell types was the IL-27-stimulated secretion of IL-6 and chemokines IP-10 and MIG. In addition, IL-27 stimulation activated STAT1 and STAT3 in HeLa and T98G cells, suggesting that IL-27 engages the STAT1/3 pathway, which then leads to the upregulation of IL-6, IP-10, and MIG. PMID- 27617646 TI - [Editorial: Proliferative Vitreo-Retinopathy]. PMID- 27617647 TI - [Ocular Hypotension: How the Retina Surgeon Sees the Causes and Therapeutic Options]. AB - Ocular hypotension is a result of a lack of production or a loss of intraocular fluid. Intraocular inflammation, drugs, or proliferative vitreoretinopathy (PVR) with overgrowth of the ciliary body can result in reduced secretion of intraocular fluid. Loss of intraocular fluid can result from external loss, such as in fistulating surgery or trauma, or internally, e.g. from cyclodialysis clefts or retinal detachment. In this review, we discuss the causal therapy of ocular hypotension: fixation of the ciliary body, removal of ciliary body membranes, surgery for PVR, choice of tamponade, possibilities and limitations of an iris diaphragm, and pharmacological options. PMID- 27617648 TI - Genetic algorithms-based inversion of multimode guided waves for cortical bone characterization. AB - Recent progress in quantitative ultrasound has exploited the multimode waveguide response of long bones. Measurements of the guided modes, along with suitable waveguide modeling, have the potential to infer strength-related factors such as stiffness (mainly determined by cortical porosity) and cortical thickness. However, the development of such model-based approaches is challenging, in particular because of the multiparametric nature of the inverse problem. Current estimation methods in the bone field rely on a number of assumptions for pairing the incomplete experimental data with the theoretical guided modes (e.g. semi automatic selection and classification of the data). The availability of an alternative inversion scheme that is user-independent is highly desirable. Thus, this paper introduces an efficient inversion method based on genetic algorithms using multimode guided waves, in which the mode-order is kept blind. Prior to its evaluation on bone, our proposal is validated using laboratory-controlled measurements on isotropic plates and bone-mimicking phantoms. The results show that the model parameters (i.e. cortical thickness and porosity) estimated from measurements on a few ex vivo human radii are in good agreement with the reference values derived from x-ray micro-computed tomography. Further, the cortical thickness estimated from in vivo measurements at the third from the distal end of the radius is in good agreement with the values delivered by site matched high-resolution x-ray peripheral computed tomography. PMID- 27617649 TI - Preliminary Evidence for Emotion Dysregulation as a Mechanism Underlying Poor Sleep Quality in Borderline Personality Disorder. AB - Sleep disturbance is common in borderline personality disorder (BPD), yet the reasons for this association are not clear. The present study sought to extend prior studies by testing emotion dysregulation as a mechanism underlying this association. We administered self-report measures of sleep quality (SQ), emotion dysregulation, and borderline features to two cross-sectional samples of undergraduates (sample 1: N = 293; sample 2: N = 188). In addition to replicating prior studies linking BPD features to poor SQ, analyses indicated that BPD features related to emotion dysregulation were most strongly correlated with poorer global SQ across both samples. Further, bootstrapping techniques revealed indirect associations by total score on the Difficulties in Emotion Regulation Scale (DERS), as well as for several of its facets (lack of strategies, lack of emotional clarity, lack of awareness). We discuss the potential clinical relevance of emotion dysregulation in the treatment of co-occurring sleep problems in BPD. PMID- 27617650 TI - Narcissistic Personality Disorder and the Structure of Common Mental Disorders. AB - Narcissistic personality disorder (NPD) shows high rates of comorbidity with mood, anxiety, substance use, and other personality disorders. Previous bivariate comorbidity investigations have left NPD multivariate comorbidity patterns poorly understood. Structural psychopathology research suggests that two transdiagnostic factors, internalizing (with distress and fear subfactors) and externalizing, account for comorbidity among common mental disorders. NPD has rarely been evaluated within this framework, with studies producing equivocal results. We investigated how NPD related to other mental disorders in the internalizing externalizing model using diagnoses from a nationally representative sample (N = 34,653). NPD was best conceptualized as a distress disorder. NPD variance accounted for by transdiagnostic factors was modest, suggesting its variance is largely unique in the context of other common mental disorders. Results clarify NPD multivariate comorbidity, suggest avenues for classification and clinical endeavors, and highlight the need to understand vulnerable and grandiose narcissism subtypes' comorbidity patterns and structural relations. PMID- 27617652 TI - Borderline Personality Disorder and the Effects of Instructed Emotional Avoidance or Acceptance in Daily Life. AB - This study examined the effects of avoidance- versus acceptance-oriented emotion regulation instructions among individuals with borderline personality disorder (BPD; n = 48), major depressive disorder (MDD; n = 54), and non-psychiatric controls (NPC; n = 50) using ecological momentary assessment. Participants were randomly assigned to either accept or avoid negative emotions, and monitored their moods, urges, and distress tolerance several times per day over 6 days. Avoidance instructions resulted in reduced negative affect and urges for maladaptive behaviors uniquely among BPD participants. Together with past research, and consistent with treatment approaches emphasizing the short-term use of skills to avoid or distract from emotions (e.g., DBT; Linehan, 1993b, 2015), these findings suggest that avoidance of negative emotions may have temporary benefits for individuals with BPD. Acceptance-oriented strategies may take longer or may require more extensive training to be beneficial for emotional functioning in everyday life in BPD. PMID- 27617651 TI - Neurocognitive Deficits in Borderline Personality Disorder: Associations With Childhood Trauma and Dimensions of Personality Psychopathology. AB - The present study evaluates the severity of neurocognitive deficits and assesses their relations with self-reported childhood trauma and dimensions of personality psychopathology in 45 outpatients with borderline personality disorder (BPD) matched to 56 non-psychiatric controls. Participants completed a comprehensive battery of neurocognitive tests, a retrospective questionnaire on early life trauma and a dimensional measure of personality psychopathology. Patients with BPD primarily showed deficits in verbal comprehension, sustained visual attention, working memory and processing speed. Comorbid posttraumatic stress disorder (PTSD) and an elevated childhood history of physical trauma were each accompanied by more severe neurocognitive deficits. There were no statistically significant associations between neurocognitive function and dimensions of personality psychopathology. These results suggest that patients with BPD display deficits mainly in higher-order thinking abilities that may be exacerbated by PTSD and substantial early life trauma. Potential relationships between neurocognitive deficits and dimensions of personality psychopathology in BPD need further examination. PMID- 27617653 TI - Where the Narcissistic Mind Wanders: Increased Self-Related Thoughts are More Positive and Future Oriented. AB - Narcissism is characterized by a preoccupation with fantasies of unlimited success, power, beauty, and similar values, which has been discussed as intra individual regulation of a grandiose, but vulnerable self-concept. To explore where the narcissistic mind wanders, we used an experience-sampling approach in a sample with large variability in pathological narcissism inventory scores. Multilevel modeling revealed (1) more mind-wandering in participants with higher levels of narcissism and (2) a difference in the content of these thoughts (more self- and other-related, past and future oriented, negative content). Critically, (3) in high levels of narcissism, the self-related thoughts were associated with more positive valence and were also more future oriented. The results demonstrate the validity of the assumed grandiose, self-absorbed view of oneself in narcissism, which includes self-indulgent fantasies of future success. We also found additional evidence for negative, past-oriented thoughts in narcissism, a dysfunctional pattern reminiscent of rumination, possibly linked to increased psychopathological vulnerability in narcissism. PMID- 27617654 TI - Coverage of the DSM-IV-TR/DSM-5 Section II Personality Disorders With the DSM-5 Dimensional Trait Model. AB - Section III of DSM-5, for emerging measures and models, includes a five-domain, 25-trait model, assessed by the Personality Inventory for DSM-5. A primary concern with respect to the trait model is its coverage of the DSM-IV-TR personality disorder syndromes (all of which were retained in DSM-5). The current study considered not only total scale scores of three independent measures of DSM IV-TR personality disorders but also the coverage of each diagnostic criterion included within six personality disorders: antisocial, borderline, avoidant, dependent, narcissistic, and obsessive-compulsive. Participants were 425 community adults, all of whom had received mental health treatment (36% currently; 75% within the past year). Results provided support for the coverage of the diagnostic criteria for the antisocial, borderline, avoidant, dependent, and narcissistic personality disorders. Coverage could perhaps be improved for a few of the criteria for obsessive-compulsive personality disorder. PMID- 27617655 TI - Prevention of food allergy - Early dietary interventions. AB - The prevalence of food allergy has increased over the last 30 years and remains a disease, which significantly impacts on the quality of life of children and their families. Several hypotheses have been formulated to explain the increasing prevalence; this review will focus on the hypothesis that dietary factors may influence the development of food allergy. Historically, the prevention of food allergy has focused on allergen avoidance. However, recent findings from interventional studies have prompted a shift in the mind set from avoidance to early introduction of potentially allergenic foods. This review aims to facilitate a better understanding of contemporary research studies that make use of early introduction of common allergenic foods into infant diets as a preventative strategy against the development of food allergy. PMID- 27617656 TI - Inverse correlation of soluble programmed cell death-1 ligand-1 (sPD-L1) with eosinophil count and clinical severity in allergic rhinitis patients. AB - BACKGROUND: T-cell response outcome is determined by co-stimulatory/inhibitory signals. Programmed cell death-1 ligand-1 (PD-L1) is a member of these co signaling molecules with known soluble form in human serum. Soluble PD-L1 (sPD L1) is also recognized in patients with some types of malignancy or autoimmune disorders, though there are few studies on sPD-L1 roles in allergic diseases. The purpose of this survey was to evaluate the association between sPD-L1 levels with eosinophil count as well as disease severity in allergic rhinitis (AR) patients. METHODS: 90 patients with AR were selected. Disease severity was determined by a modified Allergic Rhinitis and its Impact on Asthma (ARIA) classification as mild, moderate and severe. Whole blood samples were collected. Then eosinophil count and serum sPD-L1 were detected by a hematologic analyzer and a commercial ELISA kit. RESULTS: 13 (14.44%), 31 (34.44%), and 46 (51.12%) of patients had mild, moderate and severe disease, respectively. The mean levels of sPD-L1 and eosinophil count were ascertained 18.38 +/- 14.42 ng/ml and 422.43 +/- 262.26 cell/MUl. A significant inverse correlation was determined between sPD-L1 levels and eosinophil count (r = -0.364, P < 0.001). Moreover, we detected a significant negative association between sPD-L1 levels and disease severity (r = -0.384, P < 0.001). CONCLUSIONS: It is deduced that sPD-L1 can be used as a helpful marker to determine the severity of AR. Furthermore, this study indicated that sPD-L1 may have an inhibitory role in AR development, and its modulation may be considered as a useful accessory therapeutic approach for reduction of AR progression. PMID- 27617657 TI - Tunable Optical Transparency in Self-Assembled Three-Dimensional Polyhedral Graphene Oxide. AB - The origami-like self-folding process is an intellectually stimulating technique for realizing three-dimensional (3D) polyhedral free-standing graphene oxide (GO) structures. This technique allows for easy control of size, shape, and thickness of GO membranes, which in turn permits fabrication of free-standing 3D microscale polyhedral GO structures. Unlike 2D GO sheets, the 3D polyhedral free-standing GO shows a distinct optical switching behavior, resulting from a combination of the geometrical effect of the 3D hollow structure and the water-permeable multilayered GO membrane that affects the optical paths. PMID- 27617659 TI - Posttraumatic stress disorder and alcohol dependence: Epidemiology and order of onset. AB - OBJECTIVE: Posttraumatic stress disorder (PTSD) and alcohol dependence (AD) frequently co-occur; however, epidemiologic studies of temporal associations between PTSD and AD are limited. The aims of this study were (a) to investigate the bidirectional associations between PTSD and AD and (b) to examine demographic and clinical correlates of order-of-onset among individuals with PTSD and AD. METHOD: Participants were 11,103 adults (60.6% women; Mage = 48.7 years, SD = 15.9) from the National Epidemiologic Survey on Alcohol and Related Conditions who endorsed lifetime alcohol consumption and DSM-IV PTSD Criterion A trauma exposure (American Psychiatric Association, 2000). Cox proportional hazards models with time-dependent covariates were used to evaluate bidirectional associations between PTSD and AD. Sex differences were assessed using stratified analyses. RESULTS: After adjusting for demographic, trauma, and alcohol characteristics, PTSD was associated with greater likelihood of subsequent AD (hazard ratio [HR] = 1.359, 95% CI = 1.357-1.362), and AD was associated with greater likelihood of subsequent PTSD (HR = 1.274, 95% CI = 1.271-1.277). Bidirectional associations between PTSD and AD were stronger for women compared with men. Among individuals with PTSD and AD, initial onset of PTSD was associated with younger age of first potentially traumatic event. Initial onset of AD was associated with earlier initiation of alcohol use, earlier onset of heavy alcohol use, family history of alcohol problems, and history of generalized anxiety disorder and social anxiety disorder for women but not men. Initial AD was associated with lifetime panic disorder for men and women. CONCLUSIONS: Etiology of PTSD and AD is heterogeneous, and order of onset may reflect differing risk pathways. (PsycINFO Database Record PMID- 27617660 TI - Trauma, stress, and self-care in clinical training: Predictors of burnout, decline in health status, secondary traumatic stress symptoms, and compassion satisfaction. AB - [Correction Notice: An Erratum for this article was reported in Vol 9(4) of Psychological Trauma: Theory, Research, Practice, and Policy (see record 2016 54155-001). In the article, there was an error in Table 4 of the Results. The Outcomes and Predictors columns were not clearly categorized from one another. The corrected table is present in the erratum.] Objective: Courtois and Gold (2009) have called for the inclusion of trauma in the curriculum for all mental health training programs. The present study investigated the impact of trauma related content, stress, and self-care (SC) on trainees in such a program. Method: The study examined potential risk factors (trauma exposures in training [being faced with or reacting to trauma-related field work experiences and course content] and perceptions of stress in field and coursework) and protective factors (SC effort and importance) in relation to burnout (BO), health status (HS), secondary traumatic stress symptoms (STSS), and compassion satisfaction (CS) among 195 students in a graduate social work training program. Results: All students reported trauma exposures in their field placements and/or coursework, including retraumatization experiences that were associated with higher STSS and BO. Field stress and SC effort were both consistent predictors across outcomes. Higher field stress levels predicted higher BO and STSS, a greater likelihood of decline in HS, and lower CS. Lower SC effort was also associated with higher BO and STSS, and a greater likelihood of decline in HS, while higher SC effort predicted higher CS. Older students, those with traumatized field clients, and those whose field work addressed trauma, also reported higher CS. Conclusions: These findings suggest that clinical training involving trauma content can be both rewarding and stressful, and may evoke distress in some trainees. Given that learning about and working with trauma are essential to adequate clinical training, the authors suggest adopting a trauma-informed approach within clinical training programs. (PsycINFO Database Record PMID- 27617662 TI - Ipilimumab plus nivolumab for advanced melanoma. PMID- 27617661 TI - Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial. AB - BACKGROUND: In patients with platinum-sensitive recurrent serous ovarian cancer, maintenance monotherapy with the PARP inhibitor olaparib significantly improves progression-free survival versus placebo. We assessed the effect of maintenance olaparib on overall survival in patients with platinum-sensitive recurrent serous ovarian cancer, including those with BRCA1 and BRCA2 mutations (BRCAm). METHODS: In this randomised, placebo-controlled, double-blind, phase 2 trial involving 82 sites across 16 countries, patients with platinum-sensitive recurrent serous ovarian cancer who had received two or more courses of platinum-based chemotherapy and had responded to their latest regimen were randomly assigned (1:1) using a computer-generated sequence to receive oral maintenance olaparib (as capsules; 400 mg twice a day) or a matching placebo by an interactive voice response system. Patients were stratified by ancestry, time to progression on penultimate platinum, and response to most recent platinum. Patients and investigators were masked to treatment assignment by the use of unique identifiers generated during randomisation. The primary endpoint of the trial was progression-free survival. In this updated analysis, we present data for overall survival, a secondary endpoint, from the third data analysis after more than 5 years' follow-up (intention-to-treat population). We did the updated overall survival analysis, described in this Article at 77% data maturity, using a two sided alpha of 0.95%. As the study was not powered to assess overall survival, this analysis should be regarded as descriptive and the p values are nominal. We analysed randomly assigned patients for overall survival and all patients who received at least one dose of treatment for safety. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT00753545. FINDINGS: Between Aug 28, 2008, and Feb 9, 2010, 265 patients were randomly assigned to olaparib (n=136) or placebo (n=129). 136 patients had deleterious BRCAm. The data cutoff for this analysis was Sept 30, 2015. An overall survival advantage was seen with maintenance olaparib versus placebo in all patients (hazard ratio [HR] 0.73 [95% CI 0.55-0.96]; nominal p=0.025, which did not meet the required threshold for statistical significance [p<0.0095]; median overall survival was 29.8 months [95% CI 26.9-35.7] for those treated with olaparib vs 27.8 months [24.9-33.7] for those treated with placebo), and in patients with BRCAm (HR 0.62 [95% CI 0.41 0.94] nominal p=0.025; 34.9 months [95% CI 29.2-54.6] vs 30.2 months [23.1 40.7]). The overall survival data in patients with BRCA wild-type were HR 0.83 (95% CI 0.55-1.24, nominal p=0.37; 24.5 months [19.8-35.0] for those treated with olaparib vs 26.6 months [23.1-32.5] for those treated with placebo). 11 (15%) of 74 patients with BRCAm received maintenance olaparib for 5 years or more. Overall, common grade 3 or worse adverse events in the olaparib and placebo groups were fatigue (11 [8%] of 136 patients vs four [3%] of 128) and anaemia (eight [6%] vs one [1%]). 30 (22%) of 136 patients in the olaparib group and 11 (9%) of 128 patients in the placebo group reported serious adverse events. In patients treated for 2 years or more, adverse events in the olaparib and placebo groups included low-grade nausea (24 [75%] of 32 patients vs two [40%] of five), fatigue (18 [56%] of 32 vs two [40%] of five), vomiting (12 [38%] of 32 vs zero), and anaemia (eight [25%] of 32 vs one [20%] of five); generally, events were initially reported during the first 2 years of treatment. INTERPRETATION: Despite not reaching statistical significance, patients with BRCA-mutated platinum sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy after platinum-based chemotherapy appeared to have longer overall survival, supporting the reported progression-free survival benefit. Clinically useful long-term exposure to olaparib was seen with no new safety signals. Taken together, these data support both the long-term clinical benefit and tolerability of maintenance olaparib in patients with BRCA-mutated platinum-sensitive recurrent serous ovarian cancer. FUNDING: AstraZeneca. PMID- 27617663 TI - Sorafenib plus cisplatin for hepatocellular carcinoma. PMID- 27617664 TI - The fourth annual meeting of the American College of Professional Neuropsychology (ACPN) poster roster, March 9-10, 2012, Las Vegas, Nevada. PMID- 27617665 TI - A Prospective Comparative Study of Arthroscopic Versus Mini-Open Latarjet Procedure With a Minimum 2-Year Follow-up. AB - PURPOSE: To compare postoperative pain during the first postoperative week and the position of the coracoid bone block at the anterior aspect of the glenoid after the arthroscopic and the mini-open Latarjet procedure. The secondary purpose was to assess functional results and recurrence after at least 2 years of follow-up. METHODS: This comparative prospective study included patients who underwent a Latarjet-Bristow procedure for anterior shoulder instability in 2012. The Latarjet procedure was performed by a mini-open approach (G1) in one center and by an arthroscopic approach (G2) in the other. The main evaluation criterion was average shoulder pain during the first postoperative week assessed by the patient on a standard 10-cm visual analog scale (0-10). Secondary criteria were consumption of analgesics during the first week, the position of the coracoid bone block on radiograph and computed tomography scan at the 3-month follow-up and clinical outcomes (Western Ontario Score Index and new surgery) after at least 2 years of follow-up. RESULTS: Fifty-eight patients were included, 22 G1 and 36 G2, 13 women and 45 men, mean age 26.9 +/- 7.7 years. The mean follow-up was 29.8 +/- 4.4 months. There was significantly less pain in the arthroscopic Latarjet group than in the mini-open group during the first postoperative week (2.5 +/- 1.4 vs 1.2 +/- 1.2, P = .002) with comparable consumption of analgesics (P > .05). The arthroscopic Latarjet procedure resulted in a more lateral coracoid bone block (P = .04) and a better equatorial position than the mini-open technique (P = .02). Three patients underwent revision surgery (1 recurrence [2.8%], 1 block fracture, 1 screw ablation) in the arthroscopic group, none in the mini-open group (P = .54). At the final follow-up, the Western Ontario Score Index score was good in all patients (G1: 78.5 +/- 7.5% vs G2: 82.3 +/- 7%, P = .03). CONCLUSIONS: This prospective comparative study showed that the arthroscopic Latarjet procedure was significantly less painful than the mini-open procedure during the first postoperative week. The clinical outcomes were comparable after at least 2 years of follow-up. LEVEL OF EVIDENCE: Level II, prospective comparative study. PMID- 27617666 TI - Endo/exo-synergism of cellulases increases with substrate conversion. AB - Synergy between cellulolytic enzymes is important for their industrial utilization, and numerous studies have addressed the problem of how to optimize the composition of enzyme cocktails with respect to this. The degree of synergy (DS) may change with substrate conversion, and some studies have suggested a maximum in DS early in the process. Here, we systematically investigated interrelationships of DS and conversion in a model system covering a wide range of experimental conditions. The results did not reveal any correlation between DS and contact time, but when plotted against the degree of substrate conversion we saw a systematic increase in DS. We suggest that this is linked to a decreasing reactivity of the substrate. Hence, synergy became increasingly important as the recalcitrance of the remaining substrate grew. Such conversion dependent changes in DS appear to be important both in mechanistic studies and attempts to find industrial enzymes blends with optimal synergy. Biotechnol. Bioeng. 2017;114: 696 700. (c) 2016 Wiley Periodicals, Inc. PMID- 27617668 TI - Residual eDNA detection sensitivity assessed by quantitative real-time PCR in a river ecosystem. AB - Several studies have demonstrated that environmental DNA (eDNA) can be used to detect the presence of aquatic species, days to weeks after the target species has been removed. However, most studies used eDNA analysis in lentic systems (ponds or lakes), or in controlled laboratory experiments. While eDNA degrades rapidly in all aquatic systems, it also undergoes dilution effects and physical destruction in flowing systems, complicating detection in rivers. However, some eDNA (i.e. residual eDNA) can be retained in aquatic systems, even those subject to high flow regimes. Our goal was to determine residual eDNA detection sensitivity using quantitative real-time polymerase chain reaction (qRT-PCR), in a flowing, uncontrolled river after the eDNA source was removed from the system; we repeated the experiment over 2 years. Residual eDNA had the strongest signal strength at the original source site and was detectable there up to 11.5 h after eDNA source removal. Residual eDNA signal strength decreased as sampling distance downstream from the eDNA source site increased, and was no longer detectable at the source site 48 h after the eDNA source water was exhausted in both experiments. This experiment shows that residual eDNA sampled in surface water can be mapped quantitatively using qRT-PCR, which allows a more accurate spatial identification of the target species location in lotic systems, and relative residual eDNA signal strength may allow the determination of the timing of the presence of target species. PMID- 27617669 TI - Ecologic Momentary Assessment to Accomplish Real-Time Capture of Symptom Progression and the Physical and Cognitive Activities of Patients Daily Following Concussion. PMID- 27617670 TI - Design of New Complexes of Inorganic Salts Based on Lithium and Magnesium Hydroxides and Carbonates for Usage as Propellants and Flame Retardants. AB - We study the structure and electronic properties of new moieties of Li- and Mg based hydroxides and carbonates. DFT calculations at the B3LYP/6-311++G(2d,p) level show superhalogen behavior for the Li(OH)2, Mg(OH)3, Li(HCO3)2 and Mg(HCO3)2 clusters, which have adiabatic electron affinity 3.19, 3.89, 5.24, and 4.64 eV, respectively. Superalkali behavior has been identified for the Li2(OH), Li4(OH)3, Li2HCO3, and Li4(HCO3)3 clusters, which have vertical ionization potential 4.65, 3.89, 4.48, 5.08, and 4.27 eV, respectively. Calculated fragmentation energies along selected channels indicate that some of these molecules possess believable propensity as oxidizers for usage as propellants and fire suppressors. PMID- 27617671 TI - Neutrophil Extracellular Traps Promote Hypercoagulability in Patients With Sepsis. AB - BACKGROUND: Patients with sepsis commonly exhibit a hypercoagulability with high risk of venous thromboembolism (VTE). Neutrophil extracellular traps (NETs) are found to trigger inflammation and coagulation. We aim to determine whether NETs promoted the hypercoagulability and early anticoagulation reduced NETs releasing during sepsis. METHODS: In this prospective study, septic patients between September 2013 and June 2015 were included. Patients of age <18 years, acute organ failure, pregnancy, coagulation disorders, receiving anticoagulation before admission were excluded. Blood was sampled in 52 sepsis and 10 non-sepsis patients and 40 healthy controls, clinical, and hematological parameters were collected. The ability of plasma and platelets to prime neutrophils to release NETs and contribution of NETs to coagulation were assessed. NETs releasing was compared in patients with or without early coagulation, and its correlation with the risk of VTE was also evaluated. RESULTS: NETs formation in septic patients was significantly higher than controls and non-sepsis patients. Neutrophils from septic patients had significantly enhanced NETs releasing compared with those from controls or non-sepsis patients. Plasma or platelets obtained from patients induced control neutrophils to release NETs. Notably, NETs released by neutrophils from septic patients significantly increased the potency of control plasma to generate thrombin and fibrin, and this effect was attenuated by administration of DNase I. Post-treatment NETs releasing in septic patients receiving early anticoagulation within 6 h was significantly lower than patients without early anticoagulation. The NETs formation correlated positively with the VTE risk, rather than the parameters of inflammation or disease severity. CONCLUSIONS: The systemic inflammation during sepsis primes neutrophils to release NETs with increased risk of VTE. Early anticoagulation (6 h) reduces NETs releasing and may improve the coagulopathy of septic patients. PMID- 27617672 TI - Severe Sepsis Outcomes Among Hospitalizations With Inflammatory Bowel Disease. AB - BACKGROUND: Patients with inflammatory bowel disease have a unique inflammatory response to infection given the pathogenesis of these diseases and the common use of immunosuppressive therapy. AIMS: The goal of this study is to determine severe sepsis outcomes in a subgroup of visits with the comorbidities of inflammatory bowel disease. METHODS: The 2012 National Inpatient Sample database was used to identify patients with explicitly coded diagnoses of severe sepsis or septic shock. Visits with chronic inflammatory bowel disease and other inflammatory diagnoses were identified using ICD-9 codes. Sepsis outcomes of interest were identified using ICD-9 codes. RESULTS: There were 92,296 visits for severe sepsis or septic shock in the analysis. In the control group, the in-hospital mortality rate was 26.5%. Ulcerative colitis visits had a higher mortality rate (34.9%) while Crohn disease visits had lower mortality (19.6%). After adjusting for potential confounders, ulcerative colitis was independently associated with higher mortality (odds ratio [OR] 1.61, 95% CI 1.35-1.93). Conversely, Crohn disease was independently associated with lower mortality (OR 0.78, 95% CI 0.63 0.97). CONCLUSIONS: Sepsis visits with Crohn disease had improved outcomes compared with the control group. Conversely, visits with ulcerative colitis had markedly worsened sepsis-related outcomes. Further investigation is needed to determine the mechanisms underlying these clinical differences. PMID- 27617673 TI - Influence of safety motivation and climate on safety behaviour and outcomes: evidence from the Saudi Arabian construction industry. AB - PURPOSE: Over the last three decades, safety literature has focused on safety climate and its role in forecasting injuries and accidents. However, research findings regarding the relationships between safety climate and other key outcome constructs are somewhat inconsistent. Recent safety climate literature suggests that examining the role of safety motivation may help provide a better explanation of such relationships. The research presented in this article aimed to empirically analyse the relationships among safety motivation, safety climate, safety behaviour and safety outcomes within the context of the Saudi Arabian construction industry. METHOD: A conceptual model was developed to examine the relationships among four main constructs: safety motivation, safety climate, safety behaviour and safety outcomes. Based on the survey data collected in Saudi Arabia from site engineers and project managers (n = 295), statistical analyses were carried out, including confirmatory and exploratory factor analysis, and structural equation modelling to assess the model and test the hypotheses. RESULTS: The main results indicated that safety motivation could positively influence safety behaviour through safety climate, which plays a mediating role for this mechanism. The results also confirmed that safety behaviour could predict safety outcomes within the context of the Saudi Arabian construction industry. PMID- 27617674 TI - Synthesis of Site-Specific Radiolabeled Antibodies for Radioimmunotherapy via Genetic Code Expansion. AB - Radioimmunotherapy (RIT) delivers radioisotopes to antigen-expressing cells via monoantibodies for the imaging of lesions or medical therapy. The chelates are typically conjugated to the antibody through cysteine or lysine residues, resulting in heterogeneous chelate-to-antibody ratios and various conjugation sites. To overcome this heterogeneity, we have developed an approach for site specific radiolabeling of antibodies by combination of genetic code expansion and click chemistry. As a proof-of-concept study, model systems including anti-CD20 antibody rituximab, positron-emitting isotope 64Cu, and a newly synthesized bifunctional linker (4-dibenzocyclooctynol-1,4,7,10-tetraazacyclotetradecane 1,4,7,10-tetraacetic acid, DIBO-DOTA) were used. The approach consists of three steps: (1) site-specific incorporation of an azido group-bearing amino acid (NEAK) via the genetic code expansion technique at the defined sites of the antibody as a "chemical handle"; (2) site-specific and quantitative conjugation of bifunctional linkers with the antibodies under a mild condition; and (3) radiolabeling of the chelate-modified antibodies with the appropriate isotope. We used heavy-chain A122NEAK rituximab as proof-of-concept and obtained a homogeneous radioconjugate with precisely two chelates per antibody, incorporated only at the chosen sites. The conjugation did not alter the binding and pharmacokinetics of the rituximab, as indicated by in vitro assays and in vivo PET imaging. We believe our research is a good supplement to the genetic code expansion technique for the development of novel radioimmunoconjugates. PMID- 27617675 TI - Preparation of 3-Aryl-2-aminoindoles via Rhodium-Catalyzed Coupling Reaction between 2-Arylpyridines and 3-Diazoindolin-2-imines. AB - Rhodium-catalyzed coupling reaction of 3-diazoindolin-2-imines with 2 arylpyridines, 2-phenylpyrimidines, or 1-phenylpyrazoles furnished the corresponding 3-aryl-2-aminoindoles in moderate to excellent yields. A variety of functional groups were tolerant to the reaction conditions. PMID- 27617679 TI - Emissions of Per- and Polyfluoroalkyl Substances in a Textile Manufacturing Plant in China and Their Relevance for Workers' Exposure. AB - The manufacturing of high-performance fabrics requires numerous chemical treatment steps that involve the use of per- and polyfluoroalkyl substances (PFASs) to protect apparel against water, stain, and oil penetration. However, air and wastewater emissions of PFASs generated during this manufacturing are a potential threat to both factory workers and the environment. We investigated the occurrence and distribution of PFASs in wastewater, air, airborne particles, and settled dust in a textile manufacturing plant in China. PFOA and PFDA or their precursor compounds 8:2 FTOH and 10:2 FTOH were the dominant compounds in all environmental media tested, revealing that long-chain PFASs were preferably used for the manufacturing of functional garments. Besides, PFASs were detected along the textile manufacturing chain, indicating that they were used as durable water repellents and as surfactants in, for example, coating agents. The workers' exposure to FTOHs via air inhalation was up to 5 orders of magnitude higher than the background exposure of the general western population. To the best of our knowledge, this is the first study providing information regarding the emission of PFASs during the manufacturing of textiles via various environmental media. PMID- 27617677 TI - Exploring Quantitative Yeast Phenomics with Single-Cell Analysis of DNA Damage Foci. AB - A significant challenge of functional genomics is to develop methods for genome scale acquisition and analysis of cell biological data. Here, we present an integrated method that combines genome-wide genetic perturbation of Saccharomyces cerevisiae with high-content screening to facilitate the genetic description of sub-cellular structures and compartment morphology. As proof of principle, we used a Rad52-GFP marker to examine DNA damage foci in ~20 million single cells from ~5,000 different mutant backgrounds in the context of selected genetic or chemical perturbations. Phenotypes were classified using a machine learning-based automated image analysis pipeline. 345 mutants were identified that had elevated numbers of DNA damage foci, almost half of which were identified only in sensitized backgrounds. Subsequent analysis of Vid22, a protein implicated in the DNA damage response, revealed that it acts together with the Sgs1 helicase at sites of DNA damage and preferentially binds G-quadruplex regions of the genome. This approach is extensible to numerous other cell biological markers and experimental systems. PMID- 27617680 TI - Lidcombe Program Webcam Treatment for Early Stuttering: A Randomized Controlled Trial. AB - Purpose: Webcam treatment is potentially useful for health care in cases of early stuttering in which clients are isolated from specialized treatment services for geographic and other reasons. The purpose of the present trial was to compare outcomes of clinic and webcam deliveries of the Lidcombe Program treatment (Packman et al., 2015) for early stuttering. Method: The design was a parallel, open plan, noninferiority randomized controlled trial of the standard Lidcombe Program treatment and the experimental webcam Lidcombe Program treatment. Participants were 49 children aged 3 years 0 months to 5 years 11 months at the start of treatment. Primary outcomes were the percentage of syllables stuttered at 9 months postrandomization and the number of consultations to complete Stage 1 of the Lidcombe Program. Results: There was insufficient evidence of a posttreatment difference of the percentage of syllables stuttered between the standard and webcam Lidcombe Program treatments. There was insufficient evidence of a difference between the groups for typical stuttering severity measured by parents or the reported clinical relationship with the treating speech-language pathologist. Conclusions: This trial confirmed the viability of the webcam Lidcombe Program intervention. It appears to be as efficacious and economically viable as the standard, clinic Lidcombe Program treatment. PMID- 27617682 TI - Direct Introduction of a Dimesitylboryl Group Using Base-Mediated Substitution of Aryl Halides with Silyldimesitylborane. AB - The first dimesitylboryl substitution of aryl halides with a silylborane bearing a dimesitylboryl group in the presence of alkali-metal alkoxides is described. The reactions of aryl bromides or iodides with Ph2 MeSi-BMes2 and Na(OtBu) afforded the desired aryl dimesitylboranes in good to high yields and with high borylation/silylation ratios. Selective reaction of the sterically less-hindered C-Br bond of dibromoarenes provided monoborylated products. This reaction was used to rapidly construct a D-pi-A aryl dimesityl borane with a non-symmetrical biphenyl spacer. PMID- 27617678 TI - HIV Vaccine Design to Target Germline Precursors of Glycan-Dependent Broadly Neutralizing Antibodies. AB - Broadly neutralizing antibodies (bnAbs) against the N332 supersite of the HIV envelope (Env) trimer are the most common bnAbs induced during infection, making them promising leads for vaccine design. Wild-type Env glycoproteins lack detectable affinity for supersite-bnAb germline precursors and are therefore unsuitable immunogens to prime supersite-bnAb responses. We employed mammalian cell surface display to design stabilized Env trimers with affinity for germline reverted precursors of PGT121-class supersite bnAbs. The trimers maintained native-like antigenicity and structure, activated PGT121 inferred-germline B cells ex vivo when multimerized on liposomes, and primed PGT121-like responses in PGT121 inferred-germline knockin mice. Design intermediates have levels of epitope modification between wild-type and germline-targeting trimers; their mutation gradient suggests sequential immunization to induce bnAbs, in which the germline-targeting prime is followed by progressively less-mutated design intermediates and, lastly, with native trimers. The vaccine design strategies described could be utilized to target other epitopes on HIV or other pathogens. PMID- 27617685 TI - Unplanned, Postoperative Intubation in Pediatric Surgical Patients: Development and Validation of a Multivariable Prediction Model. AB - BACKGROUND: To date, the independent predictors and outcomes of unplanned postoperative intubation (UPI) in pediatric patients after noncardiac surgery are yet to be characterized. The authors aimed to identify the incidence and predictors of this event and evaluated the effect of this event on postoperative mortality. METHODS: Data of 87,920 patients from the American College of Surgeons National Surgical Quality Improvement Program Pediatric database were analyzed and assigned to derivation (n = 58,614; 66.7%) or validation (n = 29,306; 33.3%) cohorts. The derivation cohort was analyzed for the incidence and independent predictors of early UPI. The final multivariable logistic regression model was validated using the validation cohort. RESULTS: Early UPI occurred with an incidence of 0.2% in both cohorts. Among the 540 patients who experienced a UPI, 178 (33.0%) were intubated within the first 72 h after surgery. The final logistic regression model indicated operation time, severe cardiac risk factors, American Society of Anesthesiologists physical status classification more than or equal to 2, tumor involving the central nervous system, developmental delay/impaired cognitive function, past or current malignancy, and neonate status as independent predictors of early UPI. Having an early UPI was associated with an increased risk of unadjusted, all-cause 30-day mortality, demonstrating an odds ratio of 11.4 (95% CI, 5.8 to 22.4). CONCLUSIONS: Pediatric patients who experienced an early UPI after noncardiac surgery had an increased likelihood of unadjusted 30-day mortality by more than 11-fold. Identification of high-risk patients can allow for targeted intervention and potential prevention of such outcomes. PMID- 27617688 TI - Neural Correlates of Wakefulness, Sleep, and General Anesthesia: An Experimental Study in Rat. AB - BACKGROUND: Significant advances have been made in our understanding of subcortical processes related to anesthetic- and sleep-induced unconsciousness, but the associated changes in cortical connectivity and cortical neurochemistry have yet to be fully clarified. METHODS: Male Sprague-Dawley rats were instrumented for simultaneous measurement of cortical acetylcholine and electroencephalographic indices of corticocortical connectivity-coherence and symbolic transfer entropy-before, during, and after general anesthesia (propofol, n = 11; sevoflurane, n = 13). In another group of rats (n = 7), these electroencephalographic indices were analyzed during wakefulness, slow wave sleep (SWS), and rapid eye movement (REM) sleep. RESULTS: Compared to wakefulness, anesthetic-induced unconsciousness was characterized by a significant decrease in cortical acetylcholine that recovered to preanesthesia levels during recovery wakefulness. Corticocortical coherence and frontal-parietal symbolic transfer entropy in high gamma band (85 to 155 Hz) were decreased during anesthetic induced unconsciousness and returned to preanesthesia levels during recovery wakefulness. Sleep-wake states showed a state-dependent change in coherence and transfer entropy in high gamma bandwidth, which correlated with behavioral arousal: high during wakefulness, low during SWS, and lowest during REM sleep. By contrast, frontal-parietal theta connectivity during sleep-wake states was not correlated with behavioral arousal but showed an association with well established changes in cortical acetylcholine: high during wakefulness and REM sleep and low during SWS. CONCLUSIONS: Corticocortical coherence and frontal parietal connectivity in high gamma bandwidth correlates with behavioral arousal and is not mediated by cholinergic mechanisms, while theta connectivity correlates with cortical acetylcholine levels. PMID- 27617691 TI - Integration and Information: Anesthetic Unconsciousness Finds a New Bandwidth. PMID- 27617692 TI - Another Brick in (Some Kind of) Wall. PMID- 27617689 TI - Neural Correlates of Sevoflurane-induced Unconsciousness Identified by Simultaneous Functional Magnetic Resonance Imaging and Electroencephalography. AB - BACKGROUND: The neural correlates of anesthetic-induced unconsciousness have yet to be fully elucidated. Sedative and anesthetic states induced by propofol have been studied extensively, consistently revealing a decrease of frontoparietal and thalamocortical connectivity. There is, however, less understanding of the effects of halogenated ethers on functional brain networks. METHODS: The authors recorded simultaneous resting-state functional magnetic resonance imaging and electroencephalography in 16 artificially ventilated volunteers during sevoflurane anesthesia at burst suppression and 3 and 2 vol% steady-state concentrations for 700 s each to assess functional connectivity changes compared to wakefulness. Electroencephalographic data were analyzed using symbolic transfer entropy (surrogate of information transfer) and permutation entropy (surrogate of cortical information processing). Functional magnetic resonance imaging data were analyzed by an independent component analysis and a region-of interest-based analysis. RESULTS: Electroencephalographic analysis showed a significant reduction of anterior-to-posterior symbolic transfer entropy and global permutation entropy. At 2 vol% sevoflurane concentrations, frontal and thalamic networks identified by independent component analysis showed significantly reduced within-network connectivity. Primary sensory networks did not show a significant change. At burst suppression, all cortical networks showed significantly reduced functional connectivity. Region-of-interest-based thalamic connectivity at 2 vol% was significantly reduced to frontoparietal and posterior cingulate cortices but not to sensory areas. CONCLUSIONS: Sevoflurane decreased frontal and thalamocortical connectivity. The changes in blood oxygenation level dependent connectivity were consistent with reduced anterior-to-posterior directed connectivity and reduced cortical information processing. These data advance the understanding of sevoflurane-induced unconsciousness and contribute to a neural basis of electroencephalographic measures that hold promise for intraoperative anesthesia monitoring. PMID- 27617694 TI - Morning Exercise: Enhancement of Afternoon Sprint-Swimming Performance. AB - CONTEXT: An exercise bout completed several hours prior to an event may improve competitive performance later that same day. PURPOSE: To examine the influence of morning exercise on afternoon sprint-swimming performance. METHODS: Thirteen competitive swimmers (7 male, mean age 19 +/- 3 y; 6 female, mean age 17 +/- 3 y) completed a morning session of 1200 m of variedintensity swimming (SwimOnly), a combination of varied-intensity swimming and a resistance-exercise routine (SwimDry), or no morning exercise (NoEx). After a 6-h break, swimmers completed a 100-m time trial. RESULTS: Time-trial performance was faster in SwimOnly (1.6% +/ 0.6, mean +/- 90% confidence limit, P < .01) and SwimDry (1.7% +/- 0.7%, P < .01) than in NoEx. Split times for the 25- to 50-m distance were faster in both SwimOnly (1.7% +/- 1.2%, P = .02) and SwimDry (1.5% +/- 0.8%, P = .01) than in NoEx. The first 50-m stroke rate was higher in SwimOnly (0.70 +/- 0.21 Hz, mean +/- SD, P = .03) and SwimDry (0.69 +/- 0.18 Hz, P = .05) than in NoEx (0.64 +/- 0.16 Hz). Before the afternoon session, core (0.2 degrees C +/- 0.1 degrees C [mean +/- 90% confidence limit], P = .04), body (0.2 degrees C +/- 0.1 degrees C, P = .02), and skin temperatures (0.3 degrees C +/- 0.3 degrees C, P = .02) were higher in SwimDry than in NoEx. CONCLUSIONS: Completion of a morning swimming session alone or together with resistance exercise can substantially enhance sprint-swimming performance completed later the same day. PMID- 27617693 TI - Exploiting rRNA operon copy number to investigate bacterial reproductive strategies. AB - The potential for rapid reproduction is a hallmark of microbial life, but microbes in nature must also survive and compete when growth is constrained by resource availability. Successful reproduction requires different strategies when resources are scarce and when they are abundant1,2, but a systematic framework for predicting these reproductive strategies in bacteria has not been available. Here, we show that the number of ribosomal RNA operons (rrn) in bacterial genomes predicts two important components of reproduction-growth rate and growth efficiency-which are favoured under contrasting regimes of resource availability3,4. We find that the maximum reproductive rate of bacteria doubles with a doubling of rrn copy number, and the efficiency of carbon use is inversely related to maximal growth rate and rrn copy number. We also identify a feasible explanation for these patterns: the rate and yield of protein synthesis mirror the overall pattern in maximum growth rate and growth efficiency. Furthermore, comparative analysis of genomes from 1,167 bacterial species reveals that rrn copy number predicts traits associated with resource availability, including chemotaxis and genome streamlining. Genome-wide patterns of orthologous gene content covary with rrn copy number, suggesting convergent evolution in response to resource availability. Our findings imply that basic cellular processes adapt in contrasting ways to long-term differences in resource availability. They also establish a basis for predicting changes in bacterial community composition in response to resource perturbations using rrn copy number measurements5 or inferences6,7. PMID- 27617695 TI - Excitation Wavelength Independence: Toward Low-Threshold Amplified Spontaneous Emission from Carbon Nanodots. AB - Carbon nanodots (CDs) are known to be a superior type of lasing material due to their low cost, low toxicity, high photostability, and photobleaching resistance. Significant attention has been paid to synthesizing CDs with high fluorescence quantum yields (FLQYs) to achieve higher optical gains. In this report, we reveal that excitation wavelength-independent (lambdaex-independent) photoluminescence (PL) characteristics, rather than high FLQYs, should be given priority to realize CD-based light amplification. CDs with excitation wavelength-dependent (lambdaex dependent) PL characteristics and FLQYs as high as 99% and 96% were found not to exhibit amplified spontaneous emission (ASE), while those with lambdaex independent PL characteristics and FLQYs of only 38% and 82% realized ASE with low thresholds. The difficulty of achieving ASE using CDs with lambdaex-dependent PL characteristics is likely attributable to their high contents of C-O-H or C-O C groups. These groups can induce numerous localized electronic states within the n-pi* gap, which could decentralize the excited electrons, thus increasing the difficulty of population inversion. In addition, the radiative transition rates and stimulated emission cross sections of CDs with lambdaex-independent PL characteristics were found to be significantly higher than those of CDs with lambdaex-dependent PL characteristics. ASE in a planar waveguide structure, which is a practical structure for solid-state lasing devices, was also demonstrated for the first time using CDs with lambdaex-independent PL characteristics. These results provide simple and effective guidelines for synthesizing and selecting CDs for low-threshold lasing devices. PMID- 27617696 TI - Spin-resolved photoemssion study of epitaxially grown MoSe2 and WSe2 thin films. AB - Few-layer thick MoSe2 and WSe2 possess non-trivial spin textures with sizable spin splitting due to the inversion symmetry breaking embedded in the crystal structure and strong spin-orbit coupling. We report a spin-resolved photoemission study of MoSe2 and WSe2 thin film samples epitaxially grown on a bilayer graphene substrate. We only found spin polarization in the single- and trilayer samples not in the bilayer sample-mostly along the out-of-plane direction of the sample surface. The measured spin polarization is found to be strongly dependent on the light polarization as well as the measurement geometry, which reveals intricate coupling between the spin and orbital degrees of freedom in this class of material. PMID- 27617697 TI - The Epithelial-to-Mesenchymal Transition-Like Process in Glioblastoma: An Updated Systematic Review and In Silico Investigation. AB - Glioblastoma multiforme (GBM) is the most aggressive form of brain cancer due to its highly invasive nature that impedes the surgical removal of all tumor cells, making relapse inevitable. However, the mechanisms used by glioma cells to invade the surrounding tissue are still unclear. In this context, epithelial-to mesenchymal transition (EMT) has emerged as a key regulator of this invasive state and although the real relevance of this program in malignant glioma is still controversial, it has been strongly associated with GBM malignancy. EMT is a very complex process regulated by several families of transcriptional factors through many signaling pathways that form a network that allows cancer cells to acquire invasive properties and penetrate the neighboring stroma, resulting in the formation of an advantageous microenvironment for cancer progression and metastasis. In this systematic review, we focus on the molecular mechanisms of EMT including EMT-factors, drug resistance, miRNA, and new therapeutic strategies. In addition, we address controversial questions about mesenchymal shift in GBMs with a bioinformatics analysis to show that in terms of epithelial and mesenchymal phenotype, the majority of GBMs samples analyzed have a profile more mesenchymal than epithelial. If induced, this phenotype can be shifted toward an even more mesenchymal phenotype in an EMT-like process in glioma cells. A better understanding of the molecular regulation of the EMT during tumor spreading will help to provide potential therapeutic interventions to target this program when treating GBM. PMID- 27617698 TI - A Three-Component Reaction for the Synthesis of 1-Azabicyclo[3.1.0]hexane-3-enes. AB - A novel and simple synthesis of 1-azabicyclo[3.1.0]hexane-3-ene derivatives is described. The synthesis is carried out via a simple three-component reaction between aryl aldehydes, malononitrile, and hydroxylamine hydrochloride in water. Eco-friendliness, excellent product yields, short reaction time, inexpensive and readily available starting materials, and interesting reaction and products are the main advantages of this method. PMID- 27617699 TI - Tetrodotoxin-sensitive Ca2+ Currents, but No T-type Currents in Normal, Hypertrophied, and Failing Mouse Cardiomyocytes. AB - AIMS: To obtain functional evidence that ICa,T is involved in the pathogenesis of cardiac hypertrophy and heart failure. We unexpectedly identified ICa(TTX) rather than ICa,T, therefore, we adjusted our aim to encompass these findings. METHODS AND RESULTS: We investigated (1) Cav3.1 (alpha1G) transgenic (Tg) mice compared with nontransgenic (tTA-Ntg); (2) Cav3.1-deficient mice (Cav3.1) compared with wild type (Wt) after chemically and surgically induced cardiac remodeling; and (3) spontaneous hypertensive rats and thoracic aortic constriction (TAC) rats. Whole-cell patch-clamp technique was used to measure ICa in ventricular myocytes. Cav3.1-Tg expressed ICa,T (-18.35 +/- 1.02 pA/pF at -40 mV) without signs of compromised cardiac function. While we failed to detect ICa,T after hypertrophic stimuli, instead we demonstrated that both Wt and Cav3.1 mouse exhibit ICa(TTX). Using TAC rats, only 2 of 24 VMs showed ICa,T under our experimental conditions. Without TTX, ICa(TTX) occurred in VMs from Wt, spontaneous hypertensive rats, and TAC rats also. CONCLUSIONS: These findings demonstrate for the first time that mouse VMs express ICa(TTX). We suggest that future studies should take into consideration the measuring conditions when interpreting ICa,T reappearance in ventricular myocytes in response to hypertrophic stress. Contamination with ICa(TTX) could possibly confuse the relevance of the data. PMID- 27617700 TI - Relational Skills and Client Language Predict Outcome in Smoking Cessation Treatment. AB - BACKGROUND: We currently lack insight into the predictive processes of Motivational Interviewing (MI) in smoking cessation treatment. More knowledge is necessary to be able to further enhance the treatment effect in smoking cessation interventions. OBJECTIVES: To examine certain hypothesized active components of MI in smoking cessation treatment delivered in an ordinary clinical setting. METHODS: Audio-recordings of 106 smoking cessation treatment sessions were analyzed using the Motivational Interviewing Sequential Code for Observing Process Exchanges (MI-SCOPE) Coder's Manual and the Motivational Interviewing Treatment Integrity code (MITI) Manual, version 3.1. The outcome measure was self reported 6-month continuous abstinence at 12-month follow-up. RESULTS: Client Activation utterances in favor of change were positively associated with smoking cessation at follow-up. The combined category of client language expressing a Desire or a Need to continue to smoke was negatively predictive of smoking cessation. In addition, we found preliminary support for a negative interaction effect between counselors' demonstration of the spirit of MI and clients Activation utterances in favor of change. Conclusions/Importance: Our data suggest that if smoking cessation counselors cultivate client Activation utterances in favor of abstinence and softening client utterances expressing desire or perceived need to smoke, this could contribute to higher rates of treatment success. In addition, counselors' demonstration of the spirit of MI was a statistically significant predictor of outcome when the negative interaction effect between Activation utterances in favor of change and MI spirit was taken into account. These findings should be evaluated in larger studies in the future. PMID- 27617702 TI - Homogeneity of Surface Sites in Supported Single-Site Metal Catalysts: Assessment with Band Widths of Metal Carbonyl Infrared Spectra. AB - Determining and controlling the uniformity of isolated metal sites on surfaces of supports are central goals in investigations of single-site catalysts because well-defined species provide opportunities for fundamental understanding of the surface sites. CO is a useful probe of surface metal sites, often reacting with them to form metal carbonyls, the infrared spectra of which provide insights into the nature of the sites and the metal-support interface. Metals bonded to various support surface sites give broad bands in the spectra, and when narrow bands are observed, they indicate a high degree of uniformity of the metal sites. Much recent work on single-site catalysts has been done with supports that are inherently nonuniform, giving supported metal species that are therefore nonuniform. Herein we summarize values of nuCO data characterizing supported iridium gem-dicarbonyls, showing that the most nearly uniform of them are those supported on zeolites and the least uniform are those supported on metal oxides. Guided by nuCO data of supported iridium gem-dicarbonyls, we have determined new, general synthesis methods to maximize the degree of uniformity of iridium species on zeolites and on MgO. We report results for a zeolite HY-supported iridium gem dicarbonyl with full width at half-maximum values of only 4.6 and 5.2 cm-1 characterizing the symmetric and asymmetric CO stretches and implying that this is the most nearly uniform supported single-site metal catalyst. PMID- 27617703 TI - H2 Formation on Cosmic Grain Siliceous Surfaces Grafted with Fe+ : A Silsesquioxanes-Based Computational Model. AB - Cosmic siliceous dust grains are involved in the synthesis of H2 in the inter stellar medium. In this work, the dust grain siliceous surface is represented by a hydrogen Fe-metalla-silsesquioxane model of general formula: [Fe(H7 Si7 O12-n )(OH)n ]+ (n=0,1,2) where Fe+ behaves like a single-site heterogeneous catalyst grafted on a siliceous surface synthesizing H2 from H. A computational analysis is performed using two levels of theory (B3LYP-D3BJ and MP2-F12) to quantify the thermodynamic driving force of the reaction: [Fe-T7H7 ]+ +4H->[Fe-T7H7 (OH)2 ]+ +H2 . The general outcomes are: 1) H2 synthesis is thermodynamically strongly favored; 2) Fe-H / Fe-H2 barrier-less formation potential; 3) chemisorbed H-Fe leads to facile H2 synthesis at 20<=T<=100 K; 4) relative spin energetics and thermodynamic quantities between the B3LYP-D3BJ and MP2-F12 levels of theory are in qualitative agreement. The metalla-silsesquioxane model shows how Fe+ fixed on a siliceous surface can potentially catalyze H2 formation in space. PMID- 27617705 TI - Predicting Portuguese Psychology Students' Attitudes Toward the Psychological Development of Children Adopted by Lesbians and Gay Men. AB - The present study seeks to ascertain the attitudes of Portuguese psychology students (future psychologists) toward the development of children adopted by lesbian and gay parents. Each participant (N = 182) read a vignette describing an adoption of a child by lesbian and gay persons. After reading the vignette, participants rated four different aspects of the future development of the adopted child (psychosocial adjustment, victimization, psychological disturbance, and normative sexuality). Furthermore, participants were asked about their gender, interpersonal contact with lesbians and gay men, gender role attitudes, and attitudes toward lesbians and gay men. Future psychologists' attitudes toward the developmental outcomes of children adopted by lesbians and gay men were associated with negative attitudes toward non-heterosexuals, which in turn correlated to interpersonal contact with lesbians and gay men and adherence to gender conservative values. These results clearly highlight the central role of social attitudes and the need for cultural competence training of future psychologists that encourages interpersonal contact with non-heterosexuals and discourages traditional gender roles and negative attitudes toward lesbian and gay men. PMID- 27617704 TI - Discovery and Optimization of a Selective Ligand for the Switch/Sucrose Nonfermenting-Related Bromodomains of Polybromo Protein-1 by the Use of Virtual Screening and Hydration Analysis. AB - Bromodomains (BRDs) are epigenetic interaction domains currently recognized as emerging drug targets for development of anticancer or anti-inflammatory agents. In this study, development of a selective ligand of the fifth BRD of polybromo protein-1 (PB1(5)) related to switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes is presented. A compound collection was evaluated by consensus virtual screening and a hit was identified. The biophysical study of protein-ligand interactions was performed using X-ray crystallography and isothermal titration calorimetry. Collective data supported the hypothesis that affinity improvement could be achieved by enhancing interactions of the complex with the solvent. The derived SAR along with free energy calculations and a consensus hydration analysis using WaterMap and SZmap algorithms guided rational design of a set of novel analogues. The most potent analogue demonstrated high affinity of 3.3 MUM and an excellent selectivity profile, thus comprising a promising lead for the development of chemical probes targeting PB1(5). PMID- 27617706 TI - A critical assessment of the fibula flap donor site. AB - BACKGROUND: The free fibula flap has become popular for mandibular reconstruction. The purpose of this study was to propose comprehensive functional assessments of the donor site. METHODS: Thirty free fibula flaps for mandible reconstruction were prospectively enrolled in the study. Objective assessments included isokinetic testing of the ankle joint, electromyographic examination of the superficial peroneal nerve (SPN), and preoperative and postoperative foot scans. The Patient and Observer Scar Assessment Scale (POSAS) was used to subjectively assess the donor site. RESULTS: The isokinetic values of the donor side showed a significant decrease 1 year postoperatively. The results of the electromyographic test of the SPN were categorized as 3 types. The plantar center pressure shifted to the heel on the donor side 6 months postoperatively. The aesthetic outcome was satisfactory. CONCLUSION: The functional parameters of the donor site indeed declined in our assessments. Further refinements in the surgical technique are needed to improve the donor site status. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: 279-287, 2017. PMID- 27617707 TI - Funding is related to the quality, conduct, and reporting of trial reports in musculoskeletal physical therapy: A survey of 210 published trials. AB - BACKGROUND: The relationship between trial funding and methodological quality, the conduct and reporting of trials has been investigated in several medical disciplines, but remains unclear in musculoskeletal physical therapy trials. The aim of this study was to determine the association between funding and research team composition, sample size, quality, and journal impact factor of randomized controlled trial reports in musculoskeletal physical therapy. METHODS: A survey of 210 trial reports in musculoskeletal physical therapy, which were randomly selected from those published in 2011-2013 and indexed on the Physiotherapy Evidence Database (PEDro), is performed. Total PEDro score and citation details of the trial reports were downloaded from PEDro. Pairs of assessors independently extracted information about funding, sample size, and composition of the research team. Journal impact factor was downloaded by one reviewer. RESULTS: Trial funding was associated with having multiple departments in the research team (odds ratio: 1.89, 95% confidence interval: 1.03-3.49), larger sample size (median: n = 72 versus n = 50), higher quality (mean PEDro score: 6.06 versus 5.11), and publication in journals with higher impact factors (median: 2.12 versus 1.78). CONCLUSION: Trial funding was positively associated with having multiple departments represented in the research team, larger sample size, higher quality, and publication in higher impact factor journals. PMID- 27617708 TI - Complexity vs. Simplicity: The Winner Is? PMID- 27617709 TI - Sugar Industry and Coronary Heart Disease Research: A Historical Analysis of Internal Industry Documents. AB - Early warning signals of the coronary heart disease (CHD) risk of sugar (sucrose) emerged in the 1950s. We examined Sugar Research Foundation (SRF) internal documents, historical reports, and statements relevant to early debates about the dietary causes of CHD and assembled findings chronologically into a narrative case study. The SRF sponsored its first CHD research project in 1965, a literature review published in the New England Journal of Medicine, which singled out fat and cholesterol as the dietary causes of CHD and downplayed evidence that sucrose consumption was also a risk factor. The SRF set the review's objective, contributed articles for inclusion, and received drafts. The SRF's funding and role was not disclosed. Together with other recent analyses of sugar industry documents, our findings suggest the industry sponsored a research program in the 1960s and 1970s that successfully cast doubt about the hazards of sucrose while promoting fat as the dietary culprit in CHD. Policymaking committees should consider giving less weight to food industry-funded studies and include mechanistic and animal studies as well as studies appraising the effect of added sugars on multiple CHD biomarkers and disease development. PMID- 27617710 TI - A Poroelastic Fluid/Structure-Interaction Model of Cerebrospinal Fluid Dynamics in the Cord With Syringomyelia and Adjacent Subarachnoid-Space Stenosis. AB - An existing axisymmetric fluid/structure-interaction (FSI) model of the spinal cord, pia mater, subarachnoid space, and dura mater in the presence of syringomyelia and subarachnoid-space stenosis was modified to include porous solids. This allowed investigation of a hypothesis for syrinx fluid ingress from cerebrospinal fluid (CSF). Gross model deformation was unchanged by the addition of porosity, but pressure oscillated more in the syrinx and the subarachnoid space below the stenosis. The poroelastic model still exhibited elevated mean pressure in the subarachnoid space below the stenosis and in the syrinx. With realistic cord permeability, there was slight oscillatory shunt flow bypassing the stenosis via the porous tissue over the syrinx. Weak steady streaming flow occurred in a circuit involving craniocaudal flow through the stenosis and back via the syrinx. Mean syrinx volume was scarcely altered when the adjacent stenosis bisected the syrinx, but increased slightly when the syrinx was predominantly located caudal to the stenosis. The fluid content of the tissues over the syrinx oscillated, absorbing most of the radial flow seeping from the subarachnoid space so that it did not reach the syrinx. To a lesser extent, this cyclic swelling in a boundary layer of cord tissue just below the pia occurred all along the cord, representing a mechanism for exchange of interstitial fluid (ISF) and cerebrospinal fluid which could explain recent tracer findings without invoking perivascular conduits. The model demonstrates that syrinx volume increase is possible when there is subarachnoid-space stenosis and the cord and pia are permeable. PMID- 27617711 TI - Delay discounting in mild cognitive impairment. AB - INTRODUCTION: Patients with mild cognitive impairment (MCI) may make suboptimal decisions particularly in complex situations, and this could be due to temporal discounting, the tendency to prefer immediate rewards over delayed but larger rewards. The present study proposes to evaluate intertemporal preferences in MCI patients as compared to healthy controls. METHOD: Fifty-five patients with MCI and 57 healthy controls underwent neuropsychological evaluation and a delay discounting questionnaire, which evaluates three parameters: hyperbolic discounting (k), the percentage of choices for delayed and later rewards (%LL), and response consistency (Acc). RESULTS: No significant differences were found in the delay discounting questionnaire between MCI patients and controls for the three reward sizes considered, small, medium, and large, using both k and %LL parameters. There were also no differences in the response consistency, Acc, between the two groups. CONCLUSIONS: Patients with MCI perform similarly to healthy controls in a delay discounting task. Memory deficits do not notably affect intertemporal preferences. PMID- 27617712 TI - Glutamate Gated Proton-Coupled Electron Transfer Activity of a [NiFe] Hydrogenase. AB - [NiFe] hydrogenases are metalloenzymes that catalyze the reversible oxidation of H2. While electron transfer to and from the active site is understood to occur through iron-sulfur clusters, the mechanism of proton transfer is still debated. Two mechanisms for proton exchange with the active site have been proposed that involve distinct and conserved ionizable amino acid residues, one a glutamate, and the other an arginine. To examine the potential role of the conserved glutamate on active site acid-base chemistry, we mutated the putative proton donor E17 to Q in the soluble hydrogenase I from Pyrococcus furiosus using site directed mutagenesis. FTIR spectroscopy, sensitive to the CO and CN ligands of the active site, reveals catalytically active species generated upon reduction with H2, including absorption features consistent with the Nia-C intermediate. Time-resolved IR spectroscopy, which probes active site dynamics after hydride photolysis from Nia-C, indicates the E17Q mutation does not interfere with the hydride photolysis process generating known intermediates Nia-I1 and Nia-I2. Strikingly, the E17Q mutation disrupts obligatory proton-coupled electron transfer from the Nia-I1 state, thereby preventing formation of Nia-S. These results directly establish E17 as a proton donor/acceptor in the Nia-S <-> Nia-C equilibrium. PMID- 27617715 TI - Impact of psoriasis flare and remission on quality of life and work productivity: a real-world study in the USA. AB - Although psoriasis patients often report a negative impact on health-related quality of life (HRQoL) and work productivity, less is known about how disease burden varies between periods of flare and remission. The aim of this study was tocompare HRQoL and work productivity by disease activity level. Data were extracted from Adelphi 2011/2013 Disease Specific Programmes, two real world surveys of US dermatologists and psoriasis patients. HRQoL was measured using the EuroQOL 5-Dimension Health Questionnaire (EQ-5D) and Dermatology Life Quality Index (DLQI). Work productivity was measured using the Work Productivity Activity index (WPAI). Three levels of disease activity were constructed based on physician reports: remission, active not flaring, active, and flaring. Multivariable regression analyses explored the relationship between disease activity, HRQoL and work productivity, controlling for differences in demographics and comorbidities. Out of 681 psoriasis patients 24% were in remission, 62% had active disease without flaring, and 15% experienced active disease and were currently flaring. Greater disease activity was associated with worse HRQoL. EQ-5D scores decreased with more active disease (remission vs. active not flaring vs. active and flaring: 0.93 vs. 0.90 vs. 0.82; p<0.05), while DLQI scores increased (remission vs. active not flaring vs. active and flaring: 2.0 vs. 5.00 vs. 8.7; p<0.05). WPAI scores increased with disease activity indicating increased productivity loss (remission vs. active not flaring vs. active and flaring: 5.9 vs. 14.8 vs. 26.9; p<0.05). The same trends were confirmed by multivariable regression analyses. PMID- 27617714 TI - Satisfaction with current psoriasis treatment: misalignment between physician and patient perceptions. AB - Psoriasis patients often report dissatisfaction with treatment. However, the extent to which patients and their treating dermatologists are aligned regarding satisfaction with psoriasis therapy is largely unknown. This was explored using data derived from the Adelphi 2011/2013 Psoriasis Disease Specific Programmes, two real world surveys of US dermatologists and their patients. Physicians and patients independently reported their satisfaction with psoriasis control (satisfied, dissatisfied). Two levels of satisfaction alignment between physician and patient responses were constructed: aligned (same responses) and misaligned (different responses). In addition, dermatologists provided patient treatment history and disease/symptom severity whereas patients reported data on health related quality of life (HRQoL), using the EuroQOL 5-Dimension Health Questionnaire (EQ-5D) and Dermatology Life Quality Index (DLQI), and work productivity using the Work Productivity Activity index (WPAI). Multivariate regressions were employed to examine the relationship between satisfaction alignment, overall disease and symptom severity, HRQoL, and work productivity controlling for differences in patient demographics and comorbidities.From 627 paired dermatologist and psoriasis patient records, 512 (81.7%) and 115 (18.3%) cases fell into the 'aligned' and 'misaligned' groups, respectively. Compared with patients in the aligned group, those in the misaligned group had more moderate to severe psoriasis (82.3% vs. 43.7%), moderate to severe itching (45.6% vs. 27.8%), pain (23.0% vs. 10.6%), and scaling (54.8% vs. 36.1%), and had lower current biologics use (27.0% vs. 42%) (all p<0.05). The misaligned group was associated with reduced HRQoL (lower EQ-5D score: 0.86 vs. 0.91; higher DLQI score: 7.06 vs. 4.23) and greater work productivity loss (higher WPAI scores: 18.27 vs. 11.43) (all p<0.05). Multivariate analyses confirmed these results (p<0.05). Almost 1 in 5 patients were misaligned with their dermatologist's level of satisfaction with their psoriasis treatment; misalignment was associated with increased disease and symptom severity, reduced HRQoL, and reduced work productivity. PMID- 27617716 TI - Most people with psoriasis or rosacea are not being treated: a large population study. AB - When left untreated, psoriasis and rosacea can have long-term health and psychosocial implications. The purpose of this study was to estimate the percentage of Americans with psoriasis or rosacea who are not being treated. Patient data from a large claims-based database were analyzed to identify the number of patients who are treated for psoriasis or rosacea. The numbers of patients treated were compared to the estimated prevalences of these diseases in the general population, identified from previously published sources. Of the 18,632,362 patients in the database, 140,439 (0.75%) were seen for psoriasis and 165,130 (0.89%) were seen for rosacea. Based on published sources, 3.2% of Americans have psoriasis and about 5.0% have rosacea. We therefore estimated that 77% of people with psoriasis and 82% of people with rosacea are untreated. Greater awareness, resources, and community outreach projects are potential tools that could eliminate this disparity and increase the quality of life for patients with these diseases. PMID- 27617717 TI - Trends in mortality from skin diseases in the United States: skin infectious diseases are claiming more lives. AB - BackgroundAlthough there has been some excellent work published on the mortality from non-neoplastic skin disease In the United States, further analysis of trends is limited.MethodsData from the Centers for Disease Control and Prevention (CDC) for mortality abstracted from Death Certificates was obtained from the WONDER (wide-ranging online data for epidemiologic research) system from 1999 to 2014. Categorical variables were analyzed with Excel 2013 data analysis software using Chi-squared tests whereas regression was performed for trends.ResultsCrude death rates were highest in the South, especially in Mississippi and Louisiana. This work also confirmed that Blacks or African Americans had higher risk of death from skin disease, whereas Hispanic or Latinos had lower risk. Overall mortality from non-neoplastic diseases is increasing over time and significant increases in mortality from infectious and papulosquamous diseases were observed, whereas there appears to be decreasing mortality from dermatitis and miscellaneous skin disorders (ICD-10-CM L80-90).ConclusionsMortality is increasing from non neoplastic diseases, especially infectious and papulosquamous diseases. Demographic factors such age race and Hispanic or Latino ethnicity also confer differential risk. PMID- 27617718 TI - Dermatology Residents are Prescribing Tanning Bed Treatment. AB - Although 90% of dermatologists discourage the use of tanning beds, about half of psoriasis patients report using tanning beds and most of these note improvement. The purpose of this investigation was to determine if dermatology residents are advocating the tanning bed use to their patients. PMID- 27617719 TI - Dermatology Interest Groups in Medical Schools. AB - Involvement in a Dermatology Interest Group (DIG) allows students to learn about dermatology, partake in service projects, get involved in research, and ask questions about the application process for residency programs. In this article, we review the activities and member involvement of DIGs from 11 medical schools. To our knowledge, this is the first descriptive analysis of DIGs across the United States. This comparison of DIGs is not only potentially helpful for medical schools interested in establishing a DIG, but it also offers insight into how previously established DIGs could improve and have a greater impact both in individual medical schools and in the community at-large. PMID- 27617720 TI - 360-degree Evaluations on Physician Performance as an Effective Tool for Interprofessional Teams: A critical analysis of physician self-assessment as compared to nursing staff and patient evaluations of providers. AB - ImportanceThe dynamics of the medical care team, including interactions between physicians and nursing staff, has a large role to play in patient care, patient satisfaction, and future possible reimbursement determination. In order to implement changes to improve this dynamic within the medical team, it is imperative that appropriate assessments are completed to determine baseline satisfaction of our patients and nursing staff in addition to provider self assessment.ObjectiveWe aimed to investigate patient and nursing staff satisfaction with regards to provider quality of care in an outpatient academic dermatology clinic setting. We also sought out to determine provider insight in regards to satisfaction of patient and nursing staff.MethodsOur nursing staff, patients, and providers completed a questionnaire. We then compared nursing satisfaction data and patient satisfaction data with provider self-assessment to determine provider self-awareness.ResultsA total of 23 provider and nurse surveys and 562 patient satisfaction surveys were completed. Paired comparison and descriptive statistics were utilized to compare patient satisfaction, nursing satisfaction, and provider self-assessments.ConclusionsOverall, the results of the surveys demonstrated that the nursing staff and patients had high satisfaction in their interactions with the dermatology physicians. The physicians had appropriate insight into how they were perceived by the nursing staff and patients. Attending physicians as compared to resident physicians and male physicians as compared to female physicians tended to underrate themselves. PMID- 27617721 TI - Segmental neurofibromatosis and cancer: report of triple malignancy in a woman with mosaic Neurofibromatosis 1 and review of neoplasms in segmental neurofibromatosis. AB - BackgroundSegmental neurofibromatosis, referred to as mosaic neurofibromatosis 1, patients present with neurofibromas or cafe au lait macules or both in a unilateral segment of the body.PurposeA woman with segmental neurofibromatosis and triple cancer (renal cell carcinoma, mixed thyroid carcinoma, and lentigo maligna) is described and cancers observed in patients with segmental neurofibromatosis are reviewed.MethodsPubMed was used to search the following terms, separately and in combination: cancer, malignancy, mosaic, neoplasm, neurofibroma, neurofibromatosis, segment, segmental, tumor.ResultsMalignancy (13 cancers) has been observed in 11 segmental neurofibromatosis patients; one patient had three different cancers. The most common neoplasms were of neural crest origin {malignant peripheral nerve sheath tumor (3 patients) and melanoma (3 patients)] and gastrointestinal tract origin [colon (1 patient) and gastric (1 patient)]. Breast cancer, Hodgkin lymphoma, lung cancer, kidney cancer, and thyroid cancer each occurred in one patient.ConclusionsSimilar to patients with von Recklinghausen neurofibromatosis 1, individuals with segmental neurofibromatosis also have a genodermatosis-associated increased risk of developing cancer. PMID- 27617722 TI - Cosmetic tattoo pigment reaction. AB - BackgroundCutaneous reactions to tattoos are most commonly granulomatous or lichenoid.PurposeWe describe a woman who developed a lymphocytic reaction following a cosmetic tattoo procedure with black dye. The reaction occurred not only at the site of the tattoos (eyebrows and eyelash lines), but also in non tattooed skin (bilateral malar cheeks).Methods and MaterialsWe reviewed PubMed for the following terms: cosmetic, dye, granuloma, granulomatous, lichenoid, lymphocytic, perivascular, pigment, pseudolymphoma, reaction, and tattoo. We also reviewed papers containing these terms and their references.ResultsHistopathologic examination of the left eyebrow and left cheek punch biopsies showed predominantly a perivascular lymphocytic reaction secondary to exogenous tattoo pigment.ConclusionsPerivascular lymphocytic reaction is an uncommonly described complication of tattooing. Our patient had an atypical presentation since she had no prior tattoos, became symptomatic only a few days after the procedure, reacted to black dye, and involved skin both within and outside the confines of the tattoos. Her symptoms and lesions resolved after treatment with systemic and topical corticosteroids and oral antihistamines. PMID- 27617723 TI - Widespread cutaneous metastasis from ovarian serous adenocarcinoma. AB - Cutaneous metastasis can be rarely first manifestation of internal cancers; these usually develop with advanced stage malignancies. Cutaneous metastasis of ovarian cancer is rare and the majority of are seen around the pelvic region compatible with the localization of the primary ovarian tumor. Herein, we report a patient with ovarian cancer with widespread and distant cutaneous metastases showing multiple nodules and ulcers. PMID- 27617724 TI - Successful treatment of eosinophilic cellulitis with dapsone. AB - A 55-year-old woman presented with a 3-year history of recurrent episodes of pruritic cellulitis-like erythematous plaques, mostly located on the limbs. Simultaneously, fever, malaise and peripheral eosinophilia were noted. The clinical diagnosis of eosinophilic cellulitis (also known as Well's syndrome) was supported by the histopathological finding of typical "flame figures". Treatment with dapsone was initiated at a dose of 50 mg per day. After one year of follow up the patient was relapse-free. Eosinophilic cellulitis is an uncommon, recurrent inflammatory skin disease. The management is often a challenge, due to the frequent need for long-term therapy. Dapsone is an effective and safe treatment option. PMID- 27617725 TI - Kaposi Sarcoma of the eyelid as an initial manifestation of AIDS. AB - Kaposi sarcoma (KS) is a multifocal systemic disease that originates in the vascular endothelium related to Human Herpes Virus 8 (HHV-8). In the early 1980s the first series of cases of disseminated Kaposi Sarcoma in HIV infected patients were reported. However, with the advent of highly active antiretroviral therapy (HAART) since 1997, these cases are less frequently observed by clinicians. We report the case of a 40-year-old woman, presenting with two asymptomatic purpuric nodules localized in the superior and inferior left eyelids, occluding the palpebral fissure, which were present for 4 months prior to presentation. The eyelid nodules were determined to represent KS, but there were no additional cutaneous lesions. Pulmonary and gastric KS involvement was documented. Antiretroviral therapy was initiated along with pegylated liposomal doxorubicin. The nodules gradually disappeared and her immune status eventually improved. Ocular and periorbital involvement of KS associated with HIV-1 infection as the initial clinical manifestations is a rare advent. This case is important as it illustrates that disseminated KS was not to be predicted by the number or the extension of cutaneous lesions. PMID- 27617726 TI - Generalized Bullous Fixed Drug Eruption due to Bromhexine. AB - We describe a patient with a generalized bullous form of Fixed Drug Eruption (FDE) induced by bromhexine, a commonly used drug for respiratory symptoms. This is a rare association and generalized bullous FDE is also very rare. We emphasize the importance of patch tests in identifying the culprit drug. PMID- 27617727 TI - Langerhans cell histiocytosis with nail changes and multisystem disease: a case report. AB - Nail involvement in Langerhans cell histiocytosis is uncommon and is said to indicate a poor prognosis. We describe a 2-year-old boy with onycholysis, subungual hyperkeratosis, and hemorrhages on his fingernails. He also had hepatosplenomegaly and pulmonary involvement. The diagnosis of Langerhans cell histiocytosis was made by histopathologic examination of skin and liver.The role of nail involvement as an unfavorable prognostic sign is still unclear and this paper concludes that nail involvement in Langerhans cell histiocytosis is a possible sign of multisystemic involvement. PMID- 27617728 TI - Unilateral indurated plaque in the axilla: a case of metastatic breast carcinoma. AB - Breast cancer is the most commonly diagnosed cancer among American women and is also the most common internal malignancy to metastasize to the skin. Rarely, cutaneous metastases represent the first indication of breast carcinoma, putting dermatologists in an instrumental position to make the diagnosis of breast carcinoma. We report the case of a 71-year-old woman with a 10-year history of a slowly-enlarging, indurated plaque in the right axilla. Review of symptoms was significant only for occasional numbness and tingling that extended from the right axilla to the right hand. Biopsy revealed cells infiltrating in a single file between the collagen bundles in the dermis and subcutis and immunohistochemical staining consistent with a diagnosis of invasive lobular carcinoma. Subsequent work up revealed a primary breast lesion and extensive bony metastases. PMID- 27617729 TI - Congenital cartilaginous rest of the neck in a boy. AB - Congenital cartilaginous rest of the neck is a rarely encountered entity that requires surgical excision. In this case report, we describe a 12-year-old boy with asymptomatic congenital cartilaginous rest of the neck. We also discuss the associated congenital malformations that dermatologists must be aware of when caring for patients with this disease. PMID- 27617730 TI - Granuloma faciale treatment with tacrolimus. AB - We present a 40-year-old woman with a one-year history of a solitary and asymptomatic facial lesion. On physical examination a slightly infiltrated, smooth red to brown nodule was seen at the left malar region. A biopsy established the diagnosis of granuloma faciale. After two-months therapy with topical tacrolimus 0,1%, nodule was resolved. PMID- 27617731 TI - Exposure to teledermatology and resident preparedness for future practice: results of a national survey. AB - Teledermatology (TD) is an emerging modality for providing remote dermatologic care with high diagnostic and management 25 concordance compared to face-to-face clinic dermatology. TD training among dermatology residency programs in the United 26 States has not been characterized. We disseminated a survey to all dermatology residents at ACGME accredited programs in the 27 United States to explore the prevalence and distribution of TD training and trainee perceptions of TD. One hundred out of a 28 potential 1170 responses (RR 8.5%) were collected from residents in every geographic location from all years in training: 67/100 29 of residents reported that TD was practiced at their institutions, although at these sites only 21/100 residents participated in 30 clinical sessions. Residents with TD exposure were more likely to feel comfortable managing a TD consult after residency 31 (p<0.001), but were not more likely to incorporate teledermatology into their future plans. Results of this study provide insight 32 into the impact of TD exposure on resident perceptions of TD and demonstrate the need for expanding TD training across all 33 dermatology residency programs. PMID- 27617732 TI - A Quick Review of the Cutaneous Findings of the Zika Virus. AB - The current outbreak of Zika virus is a growing public health concern, especially for pregnant women. Zika virus infection may manifest as a maculopapular skin eruption that progresses rostrocaudally, with or without hemorrhagic manifestations such as petechiae and gingival bleeding. Recognizing the cutaneous findings associated with Zika virus may aid in early diagnosis, particularly in individuals at increased risk for the disease. PMID- 27617733 TI - Allergic contact dermatitis from cetearyl alcohol in Thrombocid(r) ointment. AB - Thrombocid(r) ointment (Lacer, Barcelona, Spain) is widely used in Spain and other countries for varicose veins and 22 hematomas. To our knowledge, there are no reported cases of allergic contact dermatitis following its use. Herein we present 23 two cases of allergic contact dermatitis to Thrombocid(r) ointment, owing to cetearyl alcohol. PMID- 27617734 TI - Agminated melanocytic nevus status post dabrafenib therapy for metastatic melanoma. AB - Agminated melanocytic nevus is an uncommon type of mole, characterized by a local group of macular or papular pigmented lesions, well demarcated, without a common pigmented background. This pattern has also been associated with Spitz nevi, dysplastic melanocytic nevi, and non-melanocytic lesions.We describe the onset of an acquired agminated melanocytic nevus after dabrafenib treatment. Our case highlights paradoxical MAPK activation in the setting of single-agent BRAF blockade and underscores the importance of characterizing the diverse side effects of selective BRAF inhibitors. This is the first case, to our knowledge, of agminated melanocytic nevus in association with dabrafenib. PMID- 27617735 TI - Medullary Norepinephrine Projections Release Norepinephrine into the Contralateral Bed Nucleus of the Stria Terminalis. AB - Central norepinephrine signaling influences a wide range of behavioral and physiological processes, and the ventral bed nucleus of the stria terminalis (vBNST) receives some of the densest norepinephrine innervation in the brain. Previous work describes norepinephrine neurons as projecting primarily unilaterally; however, recent evidence for cross-hemispheric catecholamine signaling challenges this idea. Here, we use fast-scan cyclic voltammetry and retrograde tracing to characterize cross-hemispheric norepinephrine signaling in the vBNST. We delivered stimulations to noradrenergic pathways originating in the A1/A2 and locus coeruleus and found hemispherically equivalent norepinephrine release in the vBNST regardless of stimulated hemisphere. Unilateral retrograde tracing revealed that medullary, but not locus coeruleus norepinephrine neurons send cross-hemispheric projections to the vBNST. Further characterization with pharmacological lesions revealed that stimulations of the locus coeruleus and its axon bundles likely elicit vBNST norepinephrine release through indirect activation. These experiments are the first to demonstrate contralateral norepinephrine release and establish that medullary, but not coerulean neurons are responsible for norepinephrine release in the vBNST. PMID- 27617739 TI - Beyond adoption status: Post-adoptive parental involvement and children's reading and math performance from kindergarten to first grade. AB - In this study, we went beyond adoption status to examine the associations between postadoption parental involvement and children's reading and math performance from kindergarten to first grade. Secondary data on a sample of adopted children and nonadopted children were drawn from the Early Childhood Longitudinal Study Kindergarten Class of 1998 to 1999 (ECLS-K). Weighted data on the children's reading performance were available for 13,900 children (181 were adopted); weighted data on the children's math performance were available for 14,128 children (184 were adopted). Descriptive data showed no group difference in reading scores at all 3 Waves but adopted children scored lower than nonadopted children in math at Wave 2 (Spring of kindergarten) and Wave 3 (Spring of first grade). However, controlling for 6 covariates, latent growth modeling showed that adoption status was unrelated to Wave 1 reading and math scores or subsequent growth rate. Rather, parents' beliefs on skills needed to succeed in kindergarten were a significant predictor of reading and math performance at Wave 1 and subsequent growth rates, and parents' educational expectation was a significant predictor of growth rate in reading and math. Our findings highlight the importance of parental involvement in adopted children's learning. (PsycINFO Database Record PMID- 27617740 TI - Guilt as a mediator between depressive symptoms and subjective age: A 17-year longitudinal study of Israeli ex-prisoners of war. AB - This longitudinal study assesses the trajectories of depressive symptoms and subjective age and the mediating role of guilt in the association between them. Two groups of aging Israeli combat veterans (M age = 57), 128 ex-prisoners of war (ex-POWs), and 106 comparable combat veterans (controls), were assessed at 3 times: 18 (Time 1 [T1]), 30 (Time 2 [T2]), and 35 (Time 3 [T3]) years after the war. They filled out self-report questionnaires on depression, guilt, and subjective age. Results revealed that significantly more ex-POWs had chronic or delayed clinical levels of depressive symptoms than did controls and that chronic and delayed depressive symptoms were associated with a higher subjective age at T3. Furthermore, the path between depressive symptoms at T1 for predicting subjective age at T3 was fully explained by levels of guilt-distress at T2. Although the mediation effect was found in both study groups, it was significantly stronger among ex-POWs than among controls. These findings suggest that not only is depression a long-term sequela of traumatic stress, it is also a risk factor for psychological aging among war veterans. Furthermore, guilt distress appears to play an important role in advancing subjective age, especially among ex-POWs. (PsycINFO Database Record PMID- 27617741 TI - Achieving social justice for children: How can children's rights thinking make a difference? AB - This article draws on themes from the author's book, Children's Rights: Toward Social Justice, that emerge from surveying children's rights issues in different childhood contexts; the family, education, child protection, and health services. The author has selected five examples of application of children's rights to a policy area and identified the implications for policy and practice. There are four core rights that cut across all children's rights issues that are mentioned before discussing specific areas. First, children, regardless of race, sex, language, religion, disability, or class, are entitled to rights. In other words, all children should enjoy their rights and should not be discriminated against. Second, "the best interests of the child" should be "a primary consideration" in actions or decisions concerning children. Third, children have the right to survival and development. And fourth, children have the right to be consulted and have their views heard in matters that affect them. PMID- 27617738 TI - Blood pressure regulation by CD4+ lymphocytes expressing choline acetyltransferase. AB - Blood pressure regulation is known to be maintained by a neuro-endocrine circuit, but whether immune cells contribute to blood pressure homeostasis has not been determined. We previously showed that CD4+ T lymphocytes that express choline acetyltransferase (ChAT), which catalyzes the synthesis of the vasorelaxant acetylcholine, relay neural signals. Here we show that these CD4+CD44hiCD62Llo T helper cells by gene expression are a distinct T-cell population defined by ChAT (CD4 TChAT). Mice lacking ChAT expression in CD4+ cells have elevated arterial blood pressure, compared to littermate controls. Jurkat T cells overexpressing ChAT (JTChAT) decreased blood pressure when infused into mice. Co-incubation of JTChAT and endothelial cells increased endothelial cell levels of phosphorylated endothelial nitric oxide synthase, and of nitrates and nitrites in conditioned media, indicating increased release of the potent vasorelaxant nitric oxide. The isolation and characterization of CD4 TChAT cells will enable analysis of the role of these cells in hypotension and hypertension, and may suggest novel therapeutic strategies by targeting cell-mediated vasorelaxation. PMID- 27617737 TI - A community-based model of rapid autopsy in end-stage cancer patients. PMID- 27617742 TI - Lay Health Worker Intervention Improved Compliance with Hepatitis B Vaccination in Asian Americans: Randomized Controlled Trial. AB - BACKGROUND: This study aimed to evaluate the effect of a lay health worker (LHW) telephone intervention on completing a series of hepatitis B virus (HBV) vaccinations among foreign-born Asian Americans in the Baltimore-Washington Metropolitan area. METHODS: During the period of April 2013 and March 2014, we recruited Asian Americans who were 18 years of age and older in the community based organizations. Of the 645 eligible participants, 600 (201 Chinese, 198 Korean, 201 Vietnamese) completed a pretest survey and received hepatitis B screening. Based on the screening results, we conducted a randomized controlled trial among those unprotected (HBsAg-/HBsAB-) by assigning them either to an intervention group (n = 124) or control group (n = 108). The intervention group received a list of resources by mails for where to get free vaccinations as well as reminder calls for vaccinations from trained LHWs, while the control group received only list of resources by mail. Seven months after mailing the HBV screening results, trained LHWs followed up with all participants by phone to ask how many of the recommended series of 3 vaccinations they had received: none, 1 or 2, or all 3 (complete). Their self-reported vaccinations were verified with the medical records. Multinomial logistic regressions were used to examine the effect of the LHW intervention. Process evaluation was conducted by asking study participants in the intervention group to evaluate the performance of the LHWs. RESULTS: After seven months, those in the intervention group were more likely to have 1 or more vaccines than the control group, compared to the no vaccination group (OR = 3.04, 95% CI, 1.16, 8.00). Also, those in the intervention group were more likely to complete a series of vaccinations than the control group, compared to the no vaccination group (OR = 7.29, 95% CI 3.39, 15.67). The most important barrier preventing them from seeking hepatitis B vaccinations was lack of time to get the vaccination. The most important promoters to getting vaccinations, among those who had vaccinations (n = 89), were our intervention program (70.8%) and self-motivation (49.4%). The majority of participants in the intervention group received the phone calls from LHWs (93%) and almost all of them got the reminder to receive vaccines (98%). CONCLUSION: The LHW intervention was successful at increasing HBV vaccinations rates among foreign-born Asian Americans. This study suggests that this culturally integrated intervention program may be useful for reducing liver cancer disparities from chronic HBV infection in high risk Asian Americans. TRIAL REGISTRATION: ClinicalTrials.gov NCT02760537. PMID- 27617743 TI - Gating That Suppresses Charge Recombination-The Role of Mono-N-Arylated Diketopyrrolopyrrole. AB - Suppressing the charge recombination (CR) that follows an efficient charge separation (CS) is of key importance for energy, electronics, and photonics applications. We focus on the role of dynamic gating for impeding CR in a molecular rotor, comprising an electron donor and acceptor directly linked via a single bond. The media viscosity has an unusual dual effect on the dynamics of CS and CR in this dyad. For solvents with intermediate viscosity, CR is 1.5-3 times slower than CS. Lowering the viscosity below ~0.6 mPa s or increasing it above ~10 mPa s makes CR 10-30 times slower than CS. Ring rotation around the donor acceptor bond can account only for the trends observed for nonviscous solvents. Media viscosity, however, affects not only torsional but also vibrational modes. Suppressing predominantly slow vibrational modes by viscous solvents can impact the rates of CS and CR to a different extent. That is, an increase in the viscosity can plausibly suppress modes that are involved in the transition from the charge-transfer (CT) to the ground state, i.e., CR, but at the same time are not important for the transition from the locally excited to the CT state, i.e., CS. These results provide a unique example of synergy between torsional and vibronic modes and their drastic effects on charge-transfer dynamics, thus setting paradigms for controlling CS and CR. PMID- 27617744 TI - Enterovirus A71 DNA-Launched Infectious Clone as a Robust Reverse Genetic Tool. AB - Enterovirus A71 (EV-A71) causes major outbreaks of hand, foot and mouth disease, and is occasionally associated with neurological complications and death in children. Reverse genetics is widely used in the field of virology for functional study of viral genes. For EV-A71, such tools are limited to clones that are transcriptionally controlled by T7/SP6 bacteriophage promoter. This is often time consuming and expensive. Here, we describe the development of infectious plasmid DNA-based EV-A71 clones, for which EV-A71 genome expression is under transcriptional control by the CMV-intermediate early promoter and SV40 transcriptional-termination signal. Transfection of this EV-A71 infectious DNA produces good virus yield similar to in vitro-transcribed EV-A71 infectious RNA, 6.4 and 5.8 log10PFU/ml, respectively. Infectious plasmid with enhanced green fluorescence protein and Nano luciferase reporter genes also produced good virus titers, with 4.3 and 5.0 log10 PFU/ml, respectively. Another infectious plasmid with both CMV and T7 promoters was also developed for easy manipulation of in vitro transcription or direct plasmid transfection. Transfection with either dual promoter infectious plasmid DNA or infectious RNA derived from this dual-promoter clone produced infectious viral particles. Incorporation of hepatitis delta virus ribozyme, which yields precise 3' ends of the DNA-launched EV-A71 genomic transcripts, increased infectious viral production. In contrast, the incorporation of hammerhead ribozyme in the DNA-launched EV-A71 resulted in lower virus yield, but improved the virus titers for T7 promoter-derived infectious RNA. This study describes rapid and robust reverse genetic tools for EV-A71. PMID- 27617745 TI - Histone Deacetylase Inhibition Restores Retinal Pigment Epithelium Function in Hyperglycemia. AB - In diabetic individuals, macular edema is a major cause of vision loss. This condition is refractory to insulin therapy and has been attributed to metabolic memory. The retinal pigment epithelium (RPE) is central to maintaining fluid balance in the retina, and this function is compromised by the activation of advanced glycation end-product receptors (RAGE). Here we provide evidence that acute administration of the RAGE agonist, glycated-albumin (gAlb) or vascular endothelial growth factor (VEGF), increased histone deacetylase (HDAC) activity in RPE cells. The administration of the class I/II HDAC inhibitor, trichostatin-A (TSA), suppressed gAlb-induced reductions in RPE transepithelial resistance (in vitro) and fluid transport (in vivo). Systemic TSA also restored normal RPE fluid transport in rats with subchronic hyperglycemia. Both gAlb and VEGF increased HDAC activity and reduced acetyl-alpha-tubulin levels. Tubastatin-A, a relatively specific antagonist of HDAC6, inhibited gAlb-induced changes in RPE cell resistance. These data are consistent with the idea that RPE dysfunction following exposure to gAlb, VEGF, or hyperglycemia is associated with increased HDAC6 activity and decreased acetyl-alpha-tubulin. Therefore, we propose inhibiting HDAC6 in the RPE as a potential therapy for preserving normal fluid homeostasis in the hyperglycemic retina. PMID- 27617746 TI - Parallel Mutations Result in a Wide Range of Cooperation and Community Consequences in a Two-Species Bacterial Consortium. AB - Multi-species microbial communities play a critical role in human health, industry, and waste remediation. Recently, the evolution of synthetic consortia in the laboratory has enabled adaptation to be addressed in the context of interacting species. Using an engineered bacterial consortium, we repeatedly evolved cooperative genotypes and examined both the predictability of evolution and the phenotypes that determine community dynamics. Eight Salmonella enterica serovar Typhimurium strains evolved methionine excretion sufficient to support growth of an Escherichia coli methionine auxotroph, from whom they required excreted growth substrates. Non-synonymous mutations in metA, encoding homoserine trans-succinylase (HTS), were detected in each evolved S. enterica methionine cooperator and were shown to be necessary for cooperative consortia growth. Molecular modeling was used to predict that most of the non-synonymous mutations slightly increase the binding affinity for HTS homodimer formation. Despite this genetic parallelism and trend of increasing protein binding stability, these metA alleles gave rise to a wide range of phenotypic diversity in terms of individual versus group benefit. The cooperators with the highest methionine excretion permitted nearly two-fold faster consortia growth and supported the highest fraction of E. coli, yet also had the slowest individual growth rates compared to less cooperative strains. Thus, although the genetic basis of adaptation was quite similar across independent origins of cooperative phenotypes, quantitative measurements of metabolite production were required to predict either the individual-level growth consequences or how these propagate to community-level behavior. PMID- 27617748 TI - Tanshinone IIA Modulates Low Density Lipoprotein Uptake via Down-Regulation of PCSK9 Gene Expression in HepG2 Cells. AB - Tanshinone IIA, one of the most pharmacologically bioactive phytochemicals isolated from Salvia miltiorrhiza Bunge, possesses several biological activities such as anti-inflammation, anti-cancer, neuroprotection and hypolipidemic activities. In this study, we aim to investigate the hypocholesterolemic effect of tanshinone IIA in hepatic cells. We demonstrated that tanshinone IIA significantly increased the amount of low-density lipoprotein receptor (LDLR) and LDL uptake activity in HepG2 cells at the post-transcriptional regulation. We further demonstrated that tanshinone IIA inhibited the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA and mature protein, which may lead to an increase the cell-surface LDLR in hepatic cells. We further identified a regulatory DNA element involved in the tanshinone IIA-mediated PCSK9 down regulation, which is located between the -411 and -336 positions of the PCSK9 promoter. Moreover, we found that tanshinone IIA markedly increased the nuclear forkhead box O3a (FoxO3a) level, enhanced FoxO3a/PCSK9 promoter complexes formation and decreased the PCSK9 promoter binding capacity of hepatocyte nuclear factor 1alpha (HNF-1alpha), resulting in suppression of PCSK9 gene expression. Finally, we found that the statin-induced PCSK9 overexpression was attenuated and the LDLR activity was elevated in a synergic manner by combination of tanshinone IIA treatment in HepG2 cells. Overall, our results reveal that the tanshinone IIA modulates LDLR level and activity via down-regulation of PCSK9 expression in hepatic cells. Our current findings provide a molecular basis of tanshinone IIA to develop PCSK9 inhibitors for cholesterol management. PMID- 27617747 TI - Uncertainty-Dependent Extinction of Fear Memory in an Amygdala-mPFC Neural Circuit Model. AB - Uncertainty of fear conditioning is crucial for the acquisition and extinction of fear memory. Fear memory acquired through partial pairings of a conditioned stimulus (CS) and an unconditioned stimulus (US) is more resistant to extinction than that acquired through full pairings; this effect is known as the partial reinforcement extinction effect (PREE). Although the PREE has been explained by psychological theories, the neural mechanisms underlying the PREE remain largely unclear. Here, we developed a neural circuit model based on three distinct types of neurons (fear, persistent and extinction neurons) in the amygdala and medial prefrontal cortex (mPFC). In the model, the fear, persistent and extinction neurons encode predictions of net severity, of unconditioned stimulus (US) intensity, and of net safety, respectively. Our simulation successfully reproduces the PREE. We revealed that unpredictability of the US during extinction was represented by the combined responses of the three types of neurons, which are critical for the PREE. In addition, we extended the model to include amygdala subregions and the mPFC to address a recent finding that the ventral mPFC (vmPFC) is required for consolidating extinction memory but not for memory retrieval. Furthermore, model simulations led us to propose a novel procedure to enhance extinction learning through re-conditioning with a stronger US; strengthened fear memory up-regulates the extinction neuron, which, in turn, further inhibits the fear neuron during re-extinction. Thus, our models increased the understanding of the functional roles of the amygdala and vmPFC in the processing of uncertainty in fear conditioning and extinction. PMID- 27617749 TI - Real-world adjustments of driver seat and head restraint in Saab 9-3 vehicles. AB - OBJECTIVE: Whiplash-associated disorder (WAD), commonly denoted whiplash injury, is a worldwide problem. These injuries occur at relatively low changes of velocity (typically <25 km/h) in impacts from all directions. Rear impacts, however, are the most common in the injury statistics. Females have a 1.5-3 times higher risk of whiplash injury than males. Improved seat design is the prevailing means of increasing the protection of whiplash injury for occupants in rear impacts. Since 1997, more advanced whiplash protection systems have been introduced on the market, the Saab Active Head Restraint (SAHR) being one of the most prominent. The SAHR-which is height adjustable-is mounted to a pressure plate in the seatback by means of a spring-resisted link mechanism. Nevertheless, studies have shown that seats equipped with reactive head restraints (such as the SAHR) have a very high injury-reducing effect for males (~60-70%) but very low or no reduction effect for females. One influencing factor could be the position of the head restraint relative to the head, because a number of studies have reported that adjustable head restraints often are incorrectly positioned by drivers. The aim was to investigate how female and male Saab drivers adjust the seat in the car they drive the most. METHODS: The seated positions of drivers in stationary conditions have been investigated in a total of 76 volunteers (34 females, 42 males) who participated in the study. Inclusion criteria incorporated driving a Saab 9-3 on a regularly basis. RESULTS: The majority of the volunteers (89%) adjusted the head restraint to any of the 3 uppermost positions and as many as 59% in the top position. The average vertical distance between the top of the head and the top of the head restraint (offset) increase linearly with increasing statures, from an average of -26 mm (head below the head restraint) for small females to an average of 82 mm (head above the head restraint) for large males. On average, the offset was 23 mm for females, which is within a satisfactory range and in accordance with recommendations; the corresponding value for males was 72 mm. The backset tended to be shorter among female volunteers (on average 27 mm) compared to the male volunteers (on average 44 mm). Moreover, the backset tended to increase with increasing statures. CONCLUSIONS: Incorrect adjustment of the head restraint cannot explain the large differences found between the sexes in the effectiveness of the SAHR system. PMID- 27617750 TI - Effects of Ultratrail Running on Skeletal-Muscle Oxygenation Dynamics. AB - PURPOSE: To quantify changes in skeletal-muscle oxygenation and pulmonary O2 uptake (VO2) after an extreme ultratrail running bout. METHODS: Before (PRE) and after (POST) the race (330-km, 24000 D+/-), profiles of vastus lateralis muscle oxygenation (ie, oxyhemoglobin [O2Hb], deoxyhemoglobin [HHb], and tissue oxygenation index [TOI]) and VO2 were determined in 14 athletes (EXP) and 12 control adults (CON) during two 4-min constant-load cycling bouts at power outputs of 1 (p1) and 1.5 (p1.5) W/kg performed in randomized order. RESULTS: At POST, normalized [HHb] values increased (p1, +38.0%; p1.5, +27.9%; P < .05), while normalized [O2Hb] (p1, -20.4%; p1.5, -14.4%; P < .05) and TOI (p1, -17.0%; p1.5, -17.7%; P < .05) decreased in EXP. VO2 values were similar (P > 0.05). An "overshoot" in normalized [HHb]:VO2 was observed, although the increase was significant only during p1.5 (+58.7%, P = .003). No difference in the aforementioned variables was noted in CON (P > .05). CONCLUSIONS: The concentric and, particularly, the eccentric loads characterizing this extreme ultratrail running bout may have led to variations in muscle structure and function, increasing the local muscle deoxygenation profile and the imbalance between O2 delivery to working muscles and muscle O2 consumption. This highlights the importance of incorporating graded training, particularly downhill bouts, to reduce the negative influence of concentric and severe eccentric loads to the microcirculatory function and to enhance the ability of runners to sustain such loading. PMID- 27617751 TI - Women with Premenstrual Dysphoria Lack the Seemingly Normal Premenstrual Right Sided Relative Dominance of 5-HTP-Derived Serotonergic Activity in the Dorsolateral Prefrontal Cortices - A Possible Cause of Disabling Mood Symptoms. AB - STUDY OBJECTIVE: To investigate potential quantitative and qualitative differences in brain serotonergic activity between women with Premenstrual Dysphoria (PMD) and asymptomatic controls. BACKGROUND: Serotonin-augmenting drugs alleviate premenstrual mood symptoms in the majority of women with PMD while serotonin-depleting diets worsen PMD symptoms, both indicating intrinsic differences in brain serotonergic activity in women with PMD compared to asymptomatic women. METHODS: Positron-emission tomography with the immediate precursor of serotonin, 5-hydroxytryptophan (5-HTP), radiolabelled by 11C in the beta-3 position, was performed in the follicular and luteal phases for 12 women with PMD and 8 control women. Brain radioactivity-a proxy for serotonin precursor uptake and synthesis-was measured in 9 regions of interest (ROIs): the right and left sides of the medial prefrontal cortex, dorsolateral prefrontal cortex, putamen and caudate nucleus, and the single "whole brain". RESULTS: There were no significant quantitative differences in brain 5-HTP-derived activity between the groups in either of the menstrual phases for any of the 9 ROIs. However, multivariate analysis revealed a significant quantitative and qualitative difference between the groups. Asymptomatic control women showed a premenstrual right sided relative increase in dorsolateral prefrontal cortex 5-HTP derived activity, whereas PMD women displayed the opposite (p = 0.0001). Menstrual phase changes in this asymmetry (premenstrual-follicular) correlated with changes in self ratings of 'irritability' for the entire group (rs = -0.595, p = 0.006). The PMD group showed a strong inverse correlation between phase changes (premenstrual follicular) in plasma levels of estradiol and phase changes in the laterality (dx/sin) of radiotracer activity in the dorsolateral prefrontal ROI (rs = -0.635; 0.027). The control group showed no such correlation. CONCLUSION: Absence of increased premenstrual right-sided relative 5-HTP-derived activity of the dorsolateral prefrontal cortices was found to strongly correlate to premenstrual irritability. A causal relationship here seems plausible, and the findings give further support to an underlying frontal brain disturbance in hormonally influenced serotonergic activity in women with PMD. Because of the small number of subjects in the study, these results should be considered preliminary, requiring verification in larger studies. PMID- 27617752 TI - On the origin of human adipocytes and the contribution of bone marrow-derived cells. AB - In the last decade, results in both animal models and humans have demonstrated that white adipocytes are generated over the entire life-span. This adds to the plasticity of adipose tissue and alterations in adipocyte turnover are linked to metabolic dysfunction. Adipocytes are derived from precursors present primarily in the perivascular areas of adipose tissue but their precise origin remains unclear. The multipotent differentiation capacity of bone marrow-derived cells (BMDC) has prompted the suggestion that BMDC may contribute to different cell tissue pools, including adipocytes. However, data in murine transplantation models have been conflicting and it has been a matter of debate whether BMDC actually differentiate into adipocytes or just fuse with resident fat cells. To resolve this controversy in humans, we recently performed a study in 65 subjects that had undergone bone marrow transplantation. Using a set of newly developed assays including single cell genome-wide analyses of mature adipocytes, we demonstrated that bone marrow contributes with approximately 10 % to the adipocyte pool. This proportion was more than doubled in obesity, suggesting that BMDC may constitute a reserve pool for adipogenesis, particularly upon weight gain. This commentary discusses the possible relevance of these and other recent findings for human pathophysiology. PMID- 27617756 TI - Characterization of mussel H2A.Z.2: a new H2A.Z variant preferentially expressed in germinal tissues from Mytilus. AB - Histones are the fundamental constituents of the eukaryotic chromatin, facilitating the physical organization of DNA in chromosomes and participating in the regulation of its metabolism. The H2A family displays the largest number of variants among core histones, including the renowned H2A.X, macroH2A, H2A.B (Bbd), and H2A.Z. This latter variant is especially interesting because of its regulatory role and its differentiation into 2 functionally divergent variants (H2A.Z.1 and H2A.Z.2), further specializing the structure and function of vertebrate chromatin. In the present work we describe, for the first time, the presence of a second H2A.Z variant (H2A.Z.2) in the genome of a non-vertebrate animal, the mussel Mytilus. The molecular and evolutionary characterization of mussel H2A.Z.1 and H2A.Z.2 histones is consistent with their functional specialization, supported on sequence divergence at promoter and coding regions as well as on varying gene expression patterns. More precisely, the expression of H2A.Z.2 transcripts in gonadal tissue and its potential upregulation in response to genotoxic stress might be mirroring the specialization of this variant in DNA repair. Overall, the findings presented in this work complement recent reports describing the widespread presence of other histone variants across eukaryotes, supporting an ancestral origin and conserved role for histone variants in chromatin. PMID- 27617758 TI - Risk Factors for Peri- and Intraventricular Hemorrhage in Very Preterm Neonates. AB - Peri- und intraventrikulare Blutungen werden in der internationalen Literatur nach Papile LA in 4 Schweregrade klassifiziert 10. Obschon diese Klassifikation auf den zu diesem Zeitpunkt gebrauchlichen computertomografischen Befunden fubetat, hat sie bis heute ihre Wertigkeit in der internationalen Literatur. Diese Blutungsentitat bei sehr unreifen Fruhgeborenen stellt sowohl fur die akute Uberlebensprognose als auch fur die langfristige Entwicklung einer der wichtigsten Risikofaktoren dar. Zahlreiche klinische Kohortenstudien belegen die dargestellten Zusammenhange bis in die aktuelle Literatur hinein bereits seit Dekaden 8. Daher war die Erfassung von Risikofaktoren und deren jeweilige Aktualisierung fur entsprechende Behandlungsperioden eine Saule der neonatologischen Forschung. Diesem Thema widmet sich die in der aktuellen Ausgabe die Untersuchung an eine bundesdeutschen Kohorte aus Ulm 15. PMID- 27617757 TI - Immune Cell Profiling of IFN-lambda Response Shows pDCs Express Highest Level of IFN-lambdaR1 and Are Directly Responsive via the JAK-STAT Pathway. AB - The interferon lambda (IFN-lambda) cytokines have well-known antiviral properties, yet their contribution to immune regulation is not well understood. Epithelial cells represent the major target cell of IFN-lambda; peripheral blood mononuclear cells are generally considered nonresponsive, with the exception of plasmacytoid dendritic cells (pDCs). In this study we aimed to define the potential for discrete subpopulations of cells to directly respond to IFN-lambda. Analysis of peripheral blood leukocytes reveals that, while pDCs uniformly express the highest levels of IFN-lambda receptor, a small proportion of B cells and monocytes also express the receptor. Nevertheless, B cells and monocytes respond poorly to IFN-lambda stimulation in vitro, with minimal STAT phosphorylation and interferon-stimulated gene (ISG) induction observed. We confirm that pDCs respond to IFN-lambda in vitro, upregulating their expression of pSTAT1, pSTAT3, and pSTAT5. However, we found that pDCs do not upregulate pSTAT6 in response to IFN-lambda treatment. Our results highlight unique aspects of the response to IFN-lambda and confirm that while the IFN-lambda receptor is expressed by a small proportion of several different circulating immune cell lineages, under normal conditions only pDCs respond to IFN-lambda stimulation with robust STAT phosphorylation and ISG induction. The difference in STAT6 responsiveness of pDCs to type I and type III interferons may help explain the divergence in their biological activities. PMID- 27617759 TI - [Survival, Medical Care and Quality of Life in Children with Trisomy 13 and 18]. AB - BACKGROUND: While infants with trisomy 13 (T13) and trisomy 18 (T18) are known to die early, parents want to know more about life expectancy and quality of life. METHODS: 30-year single-center retrospective chart analysis (1980-2010) of cytogenetically confirmed T13 and T18 cases. Mothers of infants who had lived 3 months or longer were approached to judge their infant's quality of life and talk about their experiences with medical staff. RESULTS: Data of 18/20 T13 infants and 18/21 T18 infants could be retrieved. Median survival times were 5 d for T13 and 19 d for T18. One T13 and 2T18 children survived past 1 year. Out of 5 mothers whose infants had survived at least 3 months, 4 described their infant as friendly, happy and peaceful. They observed some degree of psychomotor development and were in favour of the numerous medical and surgical interventions performed. They wished to have had a doctor coordinating these interventions and missed an active offer for psychological help. CONCLUSION: While most infants with T13 or T18 die as neonates, mothers of infants surviving longer periods of time have positive memories about their infants' quality of life. PMID- 27617755 TI - Sequence variation between 462 human individuals fine-tunes functional sites of RNA processing. AB - Recent advances in the cost-efficiency of sequencing technologies enabled the combined DNA- and RNA-sequencing of human individuals at the population-scale, making genome-wide investigations of the inter-individual genetic impact on gene expression viable. Employing mRNA-sequencing data from the Geuvadis Project and genome sequencing data from the 1000 Genomes Project we show that the computational analysis of DNA sequences around splice sites and poly-A signals is able to explain several observations in the phenotype data. In contrast to widespread assessments of statistically significant associations between DNA polymorphisms and quantitative traits, we developed a computational tool to pinpoint the molecular mechanisms by which genetic markers drive variation in RNA processing, cataloguing and classifying alleles that change the affinity of core RNA elements to their recognizing factors. The in silico models we employ further suggest RNA editing can moonlight as a splicing-modulator, albeit less frequently than genomic sequence diversity. Beyond existing annotations, we demonstrate that the ultra-high resolution of RNA-Seq combined from 462 individuals also provides evidence for thousands of bona fide novel elements of RNA processing-alternative splice sites, introns, and cleavage sites-which are often rare and lowly expressed but in other characteristics similar to their annotated counterparts. PMID- 27617760 TI - Risk Factors Associated with Intraventricular Hemorrhage in Preterm Infants with <=28 Weeks Gestational Age. AB - OBJECTIVE: To identify obstetric and neonatal risk factors associated with the development of germinal matrix-intraventricular hemorrhage (GM-IVH) in high-risk preterm neonates. METHODS AND PATIENTS: Data from 279 preterm infants (246 mothers) with a gestational age<=28+0 weeks admitted to our NICU between January 2004 and December 2009 were analyzed retrospectively. Occurrence of (GM-IVH) was diagnosed by using ultrasound and important clinical variables were extracted from the patient charts. Infants were divided into 2 groups: GM-IVH and non-GM IVH. To account for multiple gestation, generalized estimation equations (GEE) were used for univariate analysis and for the evaluation of independent risk factors. RESULTS: A low 5-min APGAR-Score, multiple birth, low arterial blood pressure at NICU admission, hypercapnia during the first 72 h of life in life and absence of any antenatal corticosteroids were found to be significant independent risk factors in the development of GM-IVH. CONCLUSION: Preterm infants with low arterial blood pressure, absence of antenatal corticosteroids, low 5-min APGAR Score, higher paCO2 within the first 3 days of life and multiple gestation were at higher risk to develop GM-IVH. Avoiding these risk factors may help to decrease the rate of GM-IVH. PMID- 27617761 TI - [Transition of Adolescents with Chronic Neurologic Disorders into Adult Health Care]. AB - BACKGROUND: Transition of care from pediatric to adult services is a complex process. Factors influencing the success of health care transition of adolescents with chronic neurological disorders are poorly understood. METHODS: Young adults with chronic neurological disorders who had been cared for in an Interdisciplinary Pediatric Center participated in this study. Using the Patient Satisfaction Questionnaire Short-form (PSQ-18) we investigated whether satisfaction of these patients with their medical care in adult services was depending on the severity and complexity of their condition. They were assigned to a group of severely disabled patients (group 1; intellectual disability or learning disability plus motor handicap or degree of disability>=80, n=11) or a group 2 of patients with milder impairment (N=39). We used descriptive and t statistics to compare both groups. RESULTS: Patients of group 1 reported slightly lower satisfaction with their present medical care in adult services (M=3.25; 95% KI=[2.96-3.55]) compared to patients of group 2 (M=3.59; 95%.KI=[3.37-3.81]; p=0.084). Satisfaction with transition was significantly lower in group 1 (M=2.65; 95% KI=[2.29-3.01]) than in group 2 (M=3.11; 95% KI=[2.89-3.33], p=0.045). The difference of mean values of 0.46 reflects a moderate effect size (Hedges' g=0.68). CONCLUSION: Health care transition of adolescent patients with chronic neurological disorders is significantly more successful in patients with minor impairment compared to patients with severe complex neurological conditions. PMID- 27617762 TI - Antibiotic Stewardship and Hospital Hygiene in German Paediatric Inpatient Facilities: A Qualitative Survey from the Paed IC Working Group. AB - BACKGROUND: Antibiotic stewardship (ABS) and hospital hygiene have both been identified as key components to increase patient safety in hospital inpatients. To set the stage for a new approach in this field, a working group of German Pediatric Infectious Disease (PID) Specialists invented the Paed IC Project in 2012. METHODS: This article summarized the results of a qualitative study using telephone interviews, to which 18 German PID specialists were invited. RESULTS: All local study coordinators and additional PID specialists from the 11 paediatric tertiary care inpatient facilities consented to participate. Only 3 of 18 participants (16.7%) are medical directors of an independent PID department. The majority of the participants agreed with the statement, that there is a need for a national clinical practice guideline (in Germany) which outlines specific paediatric aspects of ABS. In addition, concise internal clinical practice guidelines describing the most important PIDs in addition to the Handbook "Infections in Children and Adolescents" published by the DGPI were deemed necessary. 89% denied having access to any financial reimbursement allocated to cover systematic clinical audits. The hospital administration in most participating hospitals (72%) does not provide the medical specialties with personnel/financial resources to implement an ABS-program as recommended by recent guidelines. CONCLUSION: This qualitative study adds important information to adjust future strategies for ABS implementation in German paediatric inpatient care facilities. PMID- 27617763 TI - Teaching Ethics to Pediatric Residents: A Literature Analysis and Synthesis. AB - BACKGROUND: Ethics education rarely exists in pediatric resident curricula, although ethical conflicts are common in the clinical practice. Ethics education can prepare residents to successfully handle these conflicts. AIM: We searched for methods in teaching ethics to clinical and especially pediatric residents, and identified recurring barriers to ethics teaching and solutions to overcome them. DESIGN: Literature from 4 electronic databases with peer-reviewed articles was screened in 3 phases and analyzed. The literature included papers referring to applied methods or recommendations to teaching ethics to clinical residents, and on a second level focusing especially on pediatrics. An analysis and critical appraisal was conducted. RESULTS: 3 231 articles were identified. 96 papers were included. The applied learning theory, the reported teaching approaches, the barriers to teaching ethics and the provided solutions were studied and analyzed. CONCLUSIONS: We recommend case-based ethics education, including lectures, discussion, individual study; regular teaching sessions in groups, under supervision; affiliation to an ethics department, institutional and departmental support; ethics rounds and consultations not as core teaching activity; recurring problems to teaching ethics, primarily deriving from the complexity of residential duties to be addressed in advance; teaching ethics preferably in the first years of residency. We may be cautious generalizing the implementation of results on populations with different cultural backgrounds. PMID- 27617764 TI - Communicating the Improvements Developed from Critical Incident Reports is an Essential Part of CIRS. AB - BACKGROUND: The Critical Incident Reporting System (CIRS) is a tool for employees to report anonymously of near misses. Its efficiency and improvement of safety is proved by many studies. Our department introduced CIRS in 2009 and it is used frequently. As the number of reports decreased over time we asked for factors responsible for the reduced use. METHODS: All employees had access to CIRS and have been trained in several courses of instruction. Accomplished results and consequences were published in biannual newsletters. In 2014 we initiated an anonymous employee attitude survey to ask for their experience and satisfaction with CIRS. RESULTS: 88 near misses were reported since 2009. 44 (50%) reports were classified as RS1, 34 (38.6%) as RS2, and 10 (11.4%) as RS3. No RS4 reports were notified. Most reports concerned problems with administration of medication (n=26; 29.5%) and problems with technical devices (n=18; 20.5%). 75 (83%) of our employees participated in the survey. 64 (86.5%) discerned that CIRS is anonymous. 31 (41.9%) reported already a near miss. Of note, two-third didn't realize an improvement following their report. On the other hand, only half of the pollees stated to read the newsletter. CONCLUSION: Even if efficiency and advantages of CIRS are proved and undeniable, sufficient and perpetual feedback of results and improvements developed by the CIRS team and regular trainings of the employees are mandatory for the success of CIRS. PMID- 27617765 TI - Hyponatraemia in Paediatric Bronchiolitis - a Harmful Complication not to be Ignored. PMID- 27617768 TI - Comparison of the Efficiency of Rose Bengal and Methylene Blue as Photosensitizers in Photodynamic Therapy Techniques for Enterococcus faecalis Inactivation. AB - OBJECTIVE AND BACKGROUND: The aim of this in vitro study was to compare the efficiency of a photodynamic therapy (PDT) technique employing rose bengal (RB) and methylene blue (MB) as photosensitizers (PSs) to reduce the viability of Enterococcus faecalis, a well-known pathogen found in root canal systems. Currently, in several clinical applications, including in the field of endodontics, MB is employed in association with a red laser source for the photoinactivation of pathogenic bacteria. METHODS: In this study, MB was used at 0.01% (31.2 mol/L) in association with a red (660 nm) laser as the excitation source in the MB group (MBG). Alternatively, the same test was performed with RB (25 mol/L) that was associated with a green (532 nm) light laser source in the RB group (RBG). A saline solution (0.9%) was used in the control group. The colony forming units per milliliter (CFU/mL) were calculated after 24 h of incubation at 37 degrees C, and the statistical analysis was performed using ANOVA. RESULTS: The results showed a significant reduction in the CFU/mL in the RBG group (0.12 * 108) compared with the control (2.82 * 108) and MBG groups (2.66 * 108). For the concentration and laser intensity employed in the experiments, the MBG group repeatedly showed no significant reduction in bacterial counts compared with the control. Therefore, the best result regarding the reduction of E. faecalis viable cells was obtained with RB as the PS. CONCLUSIONS: PDT may be improved if RB is used in association with a green light laser source for the inactivation of E. faecalis. PMID- 27617767 TI - Dosimetry in x-ray-based breast imaging. AB - The estimation of the mean glandular dose to the breast (MGD) for x-ray based imaging modalities forms an essential part of quality control and is needed for risk estimation and for system design and optimisation. This review considers the development of methods for estimating the MGD for mammography, digital breast tomosynthesis (DBT) and dedicated breast CT (DBCT). Almost all of the methodology used employs Monte Carlo calculated conversion factors to relate the measurable quantity, generally the incident air kerma, to the MGD. After a review of the size and composition of the female breast, the various mathematical models used are discussed, with particular emphasis on models for mammography. These range from simple geometrical shapes, to the more recent complex models based on patient DBCT examinations. The possibility of patient-specific dose estimates is considered as well as special diagnostic views and the effect of breast implants. Calculations using the complex models show that the MGD for mammography is overestimated by about 30% when the simple models are used. The design and uses of breast-simulating test phantoms for measuring incident air kerma are outlined and comparisons made between patient and phantom-based dose estimates. The most widely used national and international dosimetry protocols for mammography are based on different simple geometrical models of the breast, and harmonisation of these protocols using more complex breast models is desirable. PMID- 27617769 TI - Ultrasonic degradation of sweet potato pectin and its antioxidant activity. AB - The effect of ultrasound factors (time, power, and duty cycle) on sweet potato pectin molecular weight, neutral sugar composition, pectin structure, and antioxidant activity was investigated. Sweet potato pectin dispersions (0.0025, 0.005 and 0.01g/mL) in deionized water were sonolyzed for 5, 10 and 20min to assess effect of sonication time and pectin concentration on sonolysis. For further experiments 0.0025g/mL was sonicated under varying ultrasonic power and duty cycle levels, subsequently the molecular weight, galacturonic acid content, degree of methoxylation and antioxidant activity of sonicated pectin products were investigated. Results showed that ultrasound treatment reduced pectin molecular weight, while polydispersity did not show clear trend which characterized random pectin scission, increasing duty cycle from 20% to 80% resulted in approximately threefold reduction in pectin molecular weight, increased sonication power from 100W to 400W led to significant increase in galacturonic acid content from 72.0+/-1.2% in native pectin to between 85.0+/ 3.2% and 92.0+/-2.7%, the degree of methoxylation significantly reduced from 12.0+/-3.0% to between 5.25% and 6.28%, sonication led to increase in galactose and decrease in rhamnose consistent with debranching of pectin. Moreover, sonication lead to increased antioxidant capacity, both 200W and 400W sonicated pectin having higher ORAC and FRAP values, with highest pectin concentration 4mg/mL in ORAC and 0.8mg/ml in FRAP giving substantially high antioxidant activity than native and 100W treated pectin. The ORAC value of 400W sonicated pectin increased five hold above the native pectin, while it's FRAP value was almost three fold higher than native pectin. However, ultrasound did not alter pectin primary structure as showed by FTIR and HPAEC results. The results indicated that ultrasound offers effective and green process for pectin transformation and creation of antioxidant potent pectin products. PMID- 27617770 TI - Investigation of Ti-6Al-4V alloy acoustic softening. AB - High power ultrasonic vibration is widely used for improving manufacturing processes such as machining and metal forming. High frequency mechanical vibration affects material properties and friction forces in contacting surfaces. Flow stress reduction under superimposed ultrasonic vibration is called as acoustic softening. The amount of this parameter should be determined for ultrasonic assisted metal forming processes. For determination of this parameter for workhorse Ti-6Al-4V alloy, experimental setup was designed and fabricated. Then tensile test under longitudinal ultrasonic vibration was performed for different ultrasonic powers. Results show that ultrasonic vibration has considerable effect on plastic behavior of the alloy and decreases flow stress. Also, increasing ultrasonic power leads to higher acoustic softening. Yield stress reduction up to 9.52%, ultimate stress reduction up to 4.55% and elongation up to 13% were obtained at 340W ultrasonic power. After applying ultrasonic vibrations and its termination, hardness of specimens were measured in which increase up to 9% was observed. PMID- 27617771 TI - Ultrasound assisted intensified recovery of lactose from whey based on antisolvent crystallization. AB - The current work deals with understanding the fundamental aspects of intensified recovery of lactose from paneer (cottage cheese) whey using the anti-solvent induced sonocrystallization. Ultrasonic horn (22kHz) with varying power levels over the range of 40-120W has been used for initial experiments at 100% duty cycle and two different levels of ultrasonic exposure time as 10min and 20min. Similar experiments were also performed using ultrasonic bath for the same time of exposure but with at two ultrasonic frequencies (22kHz and 33kHz). It was observed that the lactose recovery as well as purity increased with an increase in ultrasonic power at 100% duty cycle for the case of treatment time as 10min whereas the lactose recovery and purity increased only till an optimum power for the 20min treatment. In the case of ultrasonic bath, lactose purity increased with an increase in the ultrasonic frequency from 22kHz to 33kHz though the lactose recovery marginally decreased. Overall, it was observed that the maximum lactose recovery was ~98% obtained using ultrasonic horn while the maximum lactose purity was ~97%. It was also observed that maximum lactose recovery was ~94% for the case of ultrasonic bath while the maximum lactose purity was ~92%. The work has enabled to understand the optimized application of ultrasound so as to maximize both the lactose yield and purity during the recovery from whey. PMID- 27617772 TI - Therapeutic effects of intranigral transplantation of mesenchymal stem cells in rat models of Parkinson's disease. AB - Stem cell transplantation is a promising tool for the treatment of neurodegenerative disorders, including Parkinson's disease (PD); however, the therapeutic routes and mechanisms of mechanical approaches to stem cell transplantation must be explored. This study tests the therapeutic effect of transplantation of rat bone marrow mesenchymal stem cells (MSCs) into the substantia nigra (SN) of the PD rat. 5-Bromo-2-deoxyuridine-labeled rat MSCs were transplanted into the SN of the 6-hydroxydopamine-injected side of PD rat brains. The behavioral changes in PD rats were examined before and 4 and 8 weeks after MSC transplantation. The expression of tyrosine hydroxylase (TH) in the SN and the striatum and the survival and differentiation of MSCs were assessed by immunohistochemical and double immunofluorescence techniques. Abnormal behavior of PD rats was significantly improved by the administration of bone marrow MSCs, and the number of TH-positive cells in the SN and the optical density of TH positive fibers in the striatum were markedly increased. Transplanted MSCs can survive and migrate in the brain and differentiate into nestin-, neuron-specific enolase-, and GFAP-positive cells. Our findings suggest that transplantation of rat bone marrow MSCs into the SN of PD rats may provide therapeutic effects. (c) 2016 Wiley Periodicals, Inc. PMID- 27617773 TI - Brain-Derived Neurotrophic Factor Facilitates Functional Recovery from ALS Cerebral Spinal Fluid-Induced Neurodegenerative Changes in the NSC-34 Motor Neuron Cell Line. AB - BACKGROUND: The survival of motor neurons is dependent upon neurotrophic factors both during childhood and adolescence and during adult life. In disease conditions, such as in patients with amyotrophic lateral sclerosis (ALS), the mRNA levels of trophic factors like brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), fibroblast growth factor-2 (FGF-2), and vascular endothelial growth factor are downregulated. This was replicated in our in vivo experimental system following the injection of cerebral spinal fluid (CSF) of sporadic ALS (ALS-CSF) patients. OBJECTIVE: To evaluate the protective role of BDNF in a model of sporadic ALS patients. METHODS: The expressions of endogenous BDNF, its receptor TrkB, the enzyme choline acetyl transferase (ChAT), and phosphorylated neurofilaments were studied in NSC-34 cells. The calcium buffering and proapoptotic effects were assessed by calbindin-D28K and caspase-3 expression, respectively. RESULTS: ALS-CSF considerably depleted the endogenous BDNF protein, while its effect on IGF-1 and FGF-2 was inconsequential; this indirectly indicates a key role for BDNF in supporting motor neuronal survival. The exogenous supplementation of BDNF reversed autocrine expression; however, it may not be completely receptor mediated, as the TrkB levels were not restored. BDNF completely revived ChAT expression. It may inhibit apoptosis by restoring Ca2+ homeostasis, since caspase-3 and calbindin-D28K expression was back to normal. The organellar ultrastructural changes were only partially reversed. CONCLUSION: Our study provides evidence that BDNF supplementation ameliorates most but not all degenerative changes. The incomplete revival at the ultrastructural level signifies the requirement of factors other than BDNF for near-total protection of motor neurons, and, to an extent, it explains why only a partial success is achieved in clinical trials with BDNF in ALS patients. PMID- 27617776 TI - There are limits to the effects of task instructions: Making the automatic effects of task instructions context-specific takes practice. AB - Unlike other animals, humans have the unique ability to share and use verbal instructions to prepare for upcoming tasks. Recent research showed that instructions are sufficient for the automatic, reflex-like activation of responses. However, systematic studies into the limits of these automatic effects of task instructions remain relatively scarce. In this study, the authors set out to investigate whether this instruction-based automatic activation of responses can be context-dependent. Specifically, participants performed a task of which the stimulus-response rules and context (location on the screen) could either coincide or not with those of an instructed to-be-performed task (whose instructions changed every run). In 2 experiments, the authors showed that the instructed task rules had an automatic impact on performance-performance was slowed down when the merely instructed task rules did not coincide, but, importantly, this effect was not context-dependent. Interestingly, a third and fourth experiment suggests that context dependency can actually be observed, but only when practicing the task in its appropriate context for over 60 trials or after a sufficient amount of practice on a fixed context (the context was the same for all instructed tasks). Together, these findings seem to suggest that instructions can establish stimulus-response representations that have a reflexive impact on behavior but are insensitive to the context in which the task is known to be valid. Instead, context-specific task representations seem to require practice. (PsycINFO Database Record PMID- 27617775 TI - Modulation of task demands suggests that semantic processing interferes with the formation of episodic associations. AB - Although episodic and semantic memory share overlapping neural mechanisms, it remains unclear how our pre-existing semantic associations modulate the formation of new, episodic associations. When freely recalling recently studied words, people rely on both episodic and semantic associations, shown through temporal and semantic clustering of responses. We asked whether orienting participants toward semantic associations interferes with or facilitates the formation of episodic associations. We compared electroencephalographic (EEG) activity recorded during the encoding of subsequently recalled words that were either temporally or semantically clustered. Participants studied words with or without a concurrent semantic orienting task. We identified a neural signature of successful episodic association formation whereby high-frequency EEG activity (HFA, 44-100 Hz) overlying left prefrontal regions increased for subsequently temporally clustered words, but only for those words studied without a concurrent semantic orienting task. To confirm that this disruption in the formation of episodic associations was driven by increased semantic processing, we measured the neural correlates of subsequent semantic clustering. We found that HFA increased for subsequently semantically clustered words only for lists with a concurrent semantic orienting task. This dissociation suggests that increased semantic processing of studied items interferes with the neural processes that support the formation of novel episodic associations. (PsycINFO Database Record PMID- 27617777 TI - The Die Is Cast: Precision Electrophilic Modifications Contribute to Cellular Decision Making. AB - This perspective sets out to critically evaluate the scope of reactive electrophilic small molecules as unique chemical signal carriers in biological information transfer cascades. We consider these electrophilic cues as a new volatile cellular currency and compare them to canonical signaling circulation such as phosphate in terms of chemical properties, biological specificity, sufficiency, and necessity. The fact that nonenzymatic redox sensing properties are found in proteins undertaking varied cellular tasks suggests that electrophile signaling is a moonlighting phenomenon manifested within a privileged set of sensor proteins. The latest interrogations into these on-target electrophilic responses set forth a new horizon in the molecular mechanism of redox signal propagation wherein direct low-occupancy electrophilic modifications on a single sensor target are biologically sufficient to drive functional redox responses with precision timing. We detail how the various mechanisms through which redox signals function could contribute to their interesting phenotypic responses, including hormesis. PMID- 27617779 TI - Abnormal white matter integrity in synthetic cannabinoid users. AB - Synthetic cannabinoids have become increasingly popular in the last few years especially among adolescents and young adults. However, no previous studies have assessed the effects of synthetic cannabinoids on the structure of the human brain. Understanding the harms of synthetic cannabinoid use on brain structure is therefore crucial given its increasing use. Diffusion tensor imaging (DTI) was performed in 22 patients who used synthetic cannabinoids more than five times a week for at least 1 year and 18 healthy controls. Fractional anisotropy (FA) was significantly reduced in the cannabinoid group compared to controls in a cluster of white matter voxels spanning the left temporal lobe, subcortical structures and brainstem. This cluster was predominantly traversed by the inferior fronto occipital fasciculus, inferior longitudinal fasciculus, fornix, cingulum hippocampus and corticospinal tracts. Long-term use of synthetic cannabinoids is associated with white matter abnormalities in adolescents and young adults. Disturbed brain connectivity in synthetic cannabinoid users may underlie cognitive impairment and vulnerability to psychosis. PMID- 27617778 TI - Inactivation of the melanin concentrating hormone system impairs maternal behavior. AB - In order to prepare the mother for the demands of pregnancy and lactation, the maternal brain is subjected to a number of adaptations. Maternal behaviors are regulated by complex neuronal interactions. Here, we show that the melanin concentrating hormone (MCH) system is an important regulator of maternal behaviors. First, we report that melanin concentrating hormone receptor 1 knockout (MCHR1 KO) mice display a disruption of maternal behavior. Early postpartum MCHR1 KO females exhibit poor nesting, deficits in pup retrieval and maternal aggression. In addition, ablation of MCH receptors results in decreased milk production and prolactin mRNA levels. Then we show that these results are in line with those obtained in wild type mice (WT) treated with the specific MCHR1 antagonist GW803430. Furthermore, following pups retrieval, MCHR1 KO mice display a lower level of Fos expression than WT mice in the ventral tegmental area, and nucleus accumbens. With the progression of the lactation period, however, the MCHR1 KO mice improve maternal care towards their pups. This is manifested by an increase in the pups' survival rate and the decrease in pups' retrieval time beyond the second day after parturition. In conclusion, we show that the MCH system plays a significant role in the initiation of maternal behavior. In this context, MCH may play a role in integrating information from multiple sources, and connecting brain reward, homeostatic and regulatory systems. PMID- 27617780 TI - Brain functional effects of psychopharmacological treatments in bipolar disorder. AB - Functional magnetic resonance imaging (fMRI) studies have contributed to the understanding of bipolar disorder. However the effect of medication on brain activation remains poorly understood. We conducted an extensive literature review on PubMed and ScienceDirect to investigate the influence of medication in fMRI studies, including both longitudinal and cross-sectional studies, which aimed at assessing this influence. Although we reported all reviewed studies, we gave greater emphasis to studies with the most robust methodology. One hundred and forty studies matched our inclusion criteria and forty-seven studies demonstrated an effect of pharmacological treatment on fMRI blood oxygen level dependent (BOLD) signal in adults and children with bipolar disorder. Out of these studies, nineteen were longitudinal. Most of cross-sectional studies suffered from methodological bias, due to post-hoc analyses performed on a limited number of patients and did not find any effect of medication. However, both longitudinal and cross-sectional studies showing an impact of treatment tend to suggest that medication prescribed to patients with bipolar disorder mostly influenced brain activation in prefrontal regions, when measured by tasks involving emotional regulation and processing as well as non-emotional cognitive tasks. FMRI promises to elucidate potential new biomarkers in bipolar disorder and could be used to evaluate the effect of new therapeutic compounds. Further research is needed to disentangle the effect of medication and the influence of the changes in mood state on brain activation in patients with bipolar disorder. PMID- 27617781 TI - Reciprocal Effects of Positive Future Expectations, Threats to Safety, and Risk Behavior Across Adolescence. AB - We examined the reciprocal relationships among positive future expectations, expected threats to future safety, depression, and individual substance use and delinquency using 4 waves of data (N = 248-338) from African American and Latino adolescent male participants in the Chicago Youth Development Study. Individual positive future expectations and expected threats to safety were assessed at each wave and modeled as latent constructs. Individual substance use and delinquency were assessed at each wave and represented as ordinal variables ranging from low to high. Categorical autoregressive cross-lagged structural models were used to examine the hypothesized reciprocal relationships between both aspects of future expectations construct and risk behavior across adolescence. Analyses show that future expectations has important effects on youth substance use and involvement in delinquency, both of which in turn decrease positive expectations and increase expectation of threats to future safety across adolescence. Similarly, low positive expectations for the future continued to predict increased substance use and involvement in delinquency. The expected threats to safety construct was significantly correlated with delinquency within time. These effects are observed across adolescence after controlling for youth depression and race. Findings support the reciprocal effects hypothesis of a negative reinforcing cycle in the relationships between future expectations and both substance use and involvement in delinquent behavior across adolescence. The enduring nature of these relationships underscores the importance of future expectation as a potential change mechanism for intervention and prevention efforts to promote healthy development; vulnerable racial and ethnic minority male adolescents may especially benefit from such intervention. PMID- 27617782 TI - An in silico algal toxicity model with a wide applicability potential for industrial chemicals and pharmaceuticals. AB - The authors modeled the 72-h algal toxicity data of hundreds of chemicals with different modes of action as a function of chemical structures. They developed mode of action-based local quantitative structure-toxicity relationship (QSTR) models for nonpolar and polar narcotics as well as a global QSTR model with a wide applicability potential for industrial chemicals and pharmaceuticals. The present study rigorously evaluated the generated models, meeting the Organisation for Economic Co-operation and Development principles of robustness, validity, and transparency. The proposed global model had a broad structural coverage for the toxicity prediction of diverse chemicals (some of which are high-production volume chemicals) with no experimental toxicity data. The global model is potentially useful for endpoint predictions, the evaluation of algal toxicity screening, and the prioritization of chemicals, as well as for the decision of further testing and the development of risk-management measures in a scientific and regulatory frame. Environ Toxicol Chem 2017;36:1012-1019. (c) 2016 SETAC. PMID- 27617783 TI - [2016 review on catastrophic antiphospholipid syndrome]. AB - The catastrophic antiphospholipid syndrome (CAPS) develops in at least 1% of patients with antiphospholipid syndrome, either primary or associated with systemic lupus erythematosus. CAPS reveals the antiphospholipid syndrome in about 50% of cases. The CAPS is characterized by rapidly-progressive widespread thromboses mainly affecting the microvasculature in the presence of antiphospholipid antibodies. In a few days, the patients develop multiorgan failure with renal insufficiency with severe hypertension, pulmonary, cerebral, cardiac, digestive and/or cutaneous involvement. The vital prognosis is frequently engaged. CAPS is often precipitated by infectious diseases, surgical procedures and/or withdrawal or modification of the anticoagulation. CAPS overall mortality rate has decreased and is currently below 30%. The main differential diagnoses are other thrombotic microangiopathies, and heparin-induced thrombocytopenia. The treatment of CAPS consists of the association of anticoagulation and steroids, plus plasma exchange and/or intravenous immunoglobulins. Cyclophosphamide is added only in patients with active systemic lupus erythematosus. The potential contribution of some additional therapies (rituximab, eculizumab or sirolimus) needs to be assessed. The prevention of CAPS is essential and is based upon the adequate management of the perioperative period when surgery cannot be avoided, the prompt treatment and the prevention with immunization of infections and the education of patients with antiphospholipid syndrome, especially for the management of oral anticoagulants. PMID- 27617784 TI - Increased Serum Levels of IL-28 and IL-29 and the Protective Effect of IL28B rs8099917 Polymorphism in Patients with Hashimoto's Thyroiditis. AB - Hashimoto's thyroiditis (HT) is thought to result from decreased T helper type 2 (Th2) responses, leading to the progressive destruction of thyrocytes. IFN lambda1, -lambda2, and -lambda3 (also known as IL-29, IL-28A, and IL-28B, respectively) are recently described members of the IFN-lambda family and have been shown to decrease the production of Th2 cytokines in vitro. However, the role and mechanism of IFN-lambda1 in HT remain unknown. The purpose of this study was to examine whether IL29 and IL28B gene polymorphisms are susceptibility genes for the development of HT. Also, we investigated the effects of IL-29 and IL-28 serum levels in the pathogenesis of HT. Using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method, single-nucleotide polymorphisms (SNPs) of IL28B rs8099917 (IL28 G/T) and IL29 rs30461 (IL29 T/C) were studied in 99 patients with HT and 100 healthy controls. Considering the allelic distribution of the IL28 G/T polymorphism, a higher frequency of the G allele was observed in the control group versus the HT group. Thus, it was suggested that the G allele may be protective against HT pathogenesis (OR = 0.388, 95% CI = 0.217-0.693; p = 0.001). Our findings also demonstrated that there was a statistically significant difference in serum IL-28 and IL-29 levels between case and control groups (p < 0.001). Increased serum levels of IL-28 and IL-29 were found in patients with HT. However, we did not find a relationship between the IL29 gene polymorphism and HT. In conclusion, the IL28B gene polymorphism and serum IL-28 and IL-29 levels seem to play a role in the pathogenesis of HT. PMID- 27617785 TI - Surface Coating by Gold Nanoparticles on Functional Polymers: On-Demand Portable Catalysts for Suzuki Reactions. AB - We have developed new functionalized polymers capable of being easily coated by gold nanoparticles, uniformly distributed on the surface of the polymers, by simply adding a gold(III) solution in water to the polymers. The polymer supported gold nanoparticle material was used as an efficient portable and reusable catalyst for Suzuki reactions in mixed organic-aqueous solvents. PMID- 27617786 TI - Enzymatically prepared redox-responsive hydrogels as potent matrices for hepatocellular carcinoma cell spheroid formation. AB - Cellular spheroids have been received much attention in the biological and biomedical fields, especially as a base material for drug assays, regenerative medicine, and tissue engineering. Hydrogels have potential for scalable preparation of spheroids because they provide a spatial environment suitable for three-dimensional cell cultivation. Herein, the potential use of a redox responsive hydrogel as a scaffold for preparation and recovery of spheroids is reported. A hydrogel composed of poly(ethylene glycol) (PEG), which can be degraded using cysteine as a reducing agent under mild conditions, is prepared by mixing an octa-thiolated PEG derivative (8-arm PEG-SH), horseradish peroxidase and a small phenolic compound (Glycyl-L-tyrosine). Human hepatocellular carcinoma cells (HepG2) are encapsulated in the hydrogel and cellular spheroids formed by proliferation within the scaffolds. After seven days of cultivation, the size of the HepG2 spheroids reached a diameter between ~40 and 60 MUm, depending on the 8 arm PEG-SH concentration. Liver-specific functions of the HepG2 spheroids such as albumin secretion and urea production are retained at higher levels than those of cells prepared from traditional two-dimensional mono layers. These results suggest that the system presented here has potential for preparation of cellular spheroids for tissue engineering applications. PMID- 27617787 TI - Zika Virus Is More Like Rubella Than Human Immunodeficiency Virus. PMID- 27617790 TI - Temperature-Dependent Kinetic Prediction for Reactions Described by Isothermal Mathematics. AB - Most kinetic models are expressed in isothermal mathematics. This may lead unaware scientists either to the misconception that classical isothermal kinetic models cannot be used for any chemical process in an environment with a time dependent temperature profile or, even worse, to a misuse of them. In reality, classical isothermal models can be employed to make kinetic predictions for reactions in environments with time-dependent temperature profiles, provided that there is a continuity/conservation in the reaction extent at every temperature time step. In this article, fundamental analyses, illustrations, guiding tables, and examples are given to help the interested readers using either conventional isothermal reacted fraction curves or rate equations to make proper kinetic predictions for chemical reactions in environments with temperature profiles that vary, even arbitrarily, with time simply by the requirement of continuity/conservation of reaction extent whenever there is an external temperature change. PMID- 27617789 TI - Disclosure of sperm donation: a comparison between solo mother and two-parent families with identifiable donors. AB - Disclosure of donor conception to children was compared between solo mother and two-parent families with children aged 4-8 years conceived since the removal of donor anonymity in the UK. Semi-structured interviews were conducted with 31 heterosexual solo mothers and 47 heterosexual mothers with partners to investigate their decisions and experiences about identifiable donation and disclosure to their children. No significant difference was found in the proportion of mothers in each family type who had told their children about their donor conception (solo mothers 54.8%; partnered mothers 36.2%). Of those who had not told, a significantly higher proportion of solo mothers than partnered mothers intended to disclose (P < 0.05). Partnered mothers were more likely than solo mothers to feel neutral, ambivalent or negative about having used an identifiable donor (P < 0.05), and were less likely to consider children's knowledge of their genetic origins as extremely important (P < 0.05). These findings are relevant to provision of counselling services as it cannot be assumed that parents will tell their children about their origins or their entitlement to request the identity of their donor at the age of 18 years. Further qualitative research would increase understanding of solo mothers' attitudes towards disclosure. PMID- 27617791 TI - Dynamic changes of substrate reactivity and enzyme adsorption on partially hydrolyzed cellulose. AB - The enzymatic hydrolysis of cellulose is a thermodynamically challenging catalytic process that is influenced by both substrate-related and enzyme-related factors. In this study, a proteolysis approach was applied to recover and clean the partially converted cellulose at the different stages of enzymatic hydrolysis to monitor the hydrolysis rate as a function of substrate reactivity/accessibility and investigate surface characteristics of the partially converted cellulose. Enzyme-substrate interactions between individual key cellulase components from wild-type Trichoderma reesei and partially converted cellulose were followed and correlated to the enzyme adsorption capacity and dynamic sugar release. Results suggest that cellobiohydrolase CBH1 (Cel7A) and endoglucanases EG2 (Cel5A) adsorption capacities decreased as cellulose was progressively hydrolyzed, likely due to the "depletion" of binding sites. Furthermore, the degree of synergism between CBH1 and EG2 varied depending on the enzyme loading and the substrates. The results provide a better understanding of the relationship between dynamic change of substrate features and the functionality of various cellulase components during enzymatic hydrolysis. Biotechnol. Bioeng. 2017;114: 503-515. (c) 2016 Wiley Periodicals, Inc. PMID- 27617793 TI - Sensitive determination of THC and main metabolites in human plasma by means of microextraction in packed sorbent and gas chromatography-tandem mass spectrometry. AB - Cannabis is one of the most available and consumed illicit drug in the world and its identification and quantification in biological specimens can be a challenge given its low concentrations in body fluids. The present work describes a fast and fully validated procedure for the simultaneous detection and quantification of ?9-tetrahydrocannabinol (?9_THC) and its two main metabolites 11-hydroxy ?9_tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-?9- tetrahydrocannbinol (THC-COOH) in plasma samples using microextraction by packed sorbent (MEPS) and gas chromatography-tandem mass spectrometry (GC-MS/MS). A small plasma volume (0.25mL) pre-diluted (1:20), was extracted with MEPS M1 sorbent as follows: conditioning (4 cycles of 250MUL methanol and 4 cycles of 250MUL 0.1% formic acid in water); sample load (26 cycles of 250MUL); wash (100MUL of 3% acetic acid in water followed by 100MUL 5% methanol in water); and elution (6 cycles of 100MUL of 10% ammonium hydroxide in methanol). The procedure allowed the quantification of all analytes in the range of 0.1-30ng/mL. Recoveries ranged from 53 to 78% (THC), 57 to 66% (11-OH-THC) and 62 to 65% (THC-COOH), allowing the limits of detection and quantification to be set at 0.1ng/mL for all compounds. Intra-day precision and accuracy revealed coefficients of variation (CVs) lower than 10% at the studied concentrations, with a mean relative error within+/-9%, while inter day precision and accuracy showed CVs lower than 15% for all analytes at the tested concentrations, with an inaccuracy within+/-8%. PMID- 27617796 TI - Indirect Interlayer Bonding in Graphene-Topological Insulator van der Waals Heterostructure: Giant Spin-Orbit Splitting of the Graphene Dirac States. AB - van der Waals (vdW) heterostructures of two-dimensional materials exhibit properties and functionalities that can be tuned by stacking order and interlayer coupling. Although direct covalent bonding is not expected at the heterojunction, the formation of an interface nevertheless breaks the symmetries of the layers, and the orthogonal requirement of the wave functions can lead to indirect interfacial coupling, creating new properties and functionalities beyond their constituent layers. Here, we fabricate graphene/topological insulator vdW heterostructure by transferring chemical vapor deposited graphene onto Bi2Se3 grown by molecular beam epitaxy. Using scanning tunneling microscopy/spectroscopy, we observe a giant spin-orbit splitting of the graphene Dirac states up to 80 meV. Density functional theory calculations further reveal that this splitting of the graphene bands is a consequence of the breaking of inversion symmetry and the orthogonalization requirement on the overlapping wave functions at the interface, rather than simple direct bonding. Our findings reveal two intrinsic characteristics-the symmetry breaking and orthogonalization of the wave functions at the interface-that underlines the properties of vdW heterostructures. PMID- 27617797 TI - Sex differences in nonobstructive coronary artery disease: Recent insights and substantial knowledge gaps. AB - The existence of sex differences in the epidemiology, presentation, diagnosis, and management of coronary artery disease (CAD) has been a subject of growing inquiry for the past several decades. The prevailing paradigm is that the prevalence of anatomically obstructive disease of the epicardial coronary arteries is less common in women than similarly aged men, while nonobstructive and microvascular ischemic disease is more prevalent in women. Although both "patterns" of coronary atherosclerosis are associated with angina and cardiovascular events, the dominant diagnostic and therapeutic tools used in cardiology have focused on the male-predominant pattern of anatomically obstructive epicardial CAD. This has raised justified concerns about the under diagnosis and under-treatment of symptomatic women with nonobstructive CAD. However, as recent research has begun to highlight the importance of nonobstructive CAD and coronary physiology in men as well as women, adjustments to this paradigm and greater attention to nonobstructive CAD are necessary. The present article seeks to review key insights as well as substantial knowledge gaps regarding sex differences and nonobstructive CAD. PMID- 27617798 TI - Combating multidrug-resistant Gram-negative bacteria with structurally nanoengineered antimicrobial peptide polymers. AB - With the recent emergence of reports on resistant Gram-negative 'superbugs', infections caused by multidrug-resistant (MDR) Gram-negative bacteria have been named as one of the most urgent global health threats due to the lack of effective and biocompatible drugs. Here, we show that a class of antimicrobial agents, termed 'structurally nanoengineered antimicrobial peptide polymers' (SNAPPs) exhibit sub-MUM activity against all Gram-negative bacteria tested, including ESKAPE and colistin-resistant and MDR (CMDR) pathogens, while demonstrating low toxicity. SNAPPs are highly effective in combating CMDR Acinetobacter baumannii infections in vivo, the first example of a synthetic antimicrobial polymer with CMDR Gram-negative pathogen efficacy. Furthermore, we did not observe any resistance acquisition by A. baumannii (including the CMDR strain) to SNAPPs. Comprehensive analyses using a range of microscopy and (bio)assay techniques revealed that the antimicrobial activity of SNAPPs proceeds via a multimodal mechanism of bacterial cell death by outer membrane destabilization, unregulated ion movement across the cytoplasmic membrane and induction of the apoptotic-like death pathway, possibly accounting for why we did not observe resistance to SNAPPs in CMDR bacteria. Overall, SNAPPs show great promise as low-cost and effective antimicrobial agents and may represent a weapon in combating the growing threat of MDR Gram-negative bacteria. PMID- 27617799 TI - Three Complementary Approaches to Characterize Buprenorphine Misuse. AB - BACKGROUND: In France, buprenorphine has been available for opioid maintenance therapy since 1996 and since then its misuse has been continuously evaluated by the French health authorities. OBJECTIVES: To characterize buprenorphine misuse in Languedoc-Roussillon (LR) region, using three different approaches. METHODS: Three different data sources were analyzed : (i) spontaneous reports (NotS) of buprenorphine misuse or dependence, (ii) a specific periodic survey from specialized care centers (OPPIDUM) over 11 years (2002-2012) and (iii) a drug reimbursement database (DRB). RESULTS: A total of 209 spontaneous reports were collected. The main type of buprenorphine misuse was use by an unintended route of administration. The main complications notified were directly related to the injection of buprenorphine. NotS enabled the collection of data about severe clinical complications or new diversion phenomenon. The OPPIDUM LR survey revealed a decrease in the buprenorphine misuse indicator through the study period. The DRB analysis identified one subgroup of patients with a buprenorphine deviant behavior, characterized by a significantly greater number of dispensing episodes, pharmacies, prescribers, daily dose and switch between buprenorphine forms (princeps and generic). The DRB analysis provides data on buprenorphine diversion in the context of outpatients care. CONCLUSION: The three complementary approaches allowed us to characterize buprenorphine misuse in LR area. The three approaches are complementary because each data source provides different types of information. PMID- 27617800 TI - Pilot physiology, cognition and flight performance during flight simulation exposed to a 3810-m hypoxic condition. AB - BACKGROUND: Hypoxia is a physiological state defined as a reduction in the distribution of oxygen to the tissues of the body. It has been considered a major factor in aviation safety worldwide because of its potential for pilot disorientation. Pilots are able to operate aircrafts up to 3810 m without the use of supplemental oxygen and may exhibit symptoms associated with hypoxia. OBJECTIVE: To determine the effects of 3810 m on physiology, cognition and performance in pilots during a flight simulation. METHODS: Ten healthy male pilots engaged in a counterbalanced experimental protocol comparing a 0-m normoxic condition (NORM) with a 3810-m hypoxic condition (HYP) on pilot physiology, cognition and flight performance. RESULTS: Repeated-measures analysis of variance demonstrated a significant (p <= 0.05) time by condition interaction for physiological and cognitive alterations during HYP. A paired-samples t test demonstrated no differences in pilot performance (p >= 0.05) between conditions. CONCLUSION: Pilots exhibited physiological and cognitive impairments; however, pilot performance was not affected by HYP. PMID- 27617801 TI - Hodgkin lymphoma of the maxillary sinus: A diagnostic trap? PMID- 27617802 TI - Citrobacter freundii as a test platform for recombinant cellulose degradation systems. AB - : Cellulosic biomass represents a huge reservoir of renewable carbon, but converting it into useful products is challenging. Attempts to transfer cellulose degradation capability to industrially useful micro-organisms have met with limited success, possibly due to poorly understood synergy between multiple cellulases. This is best studied by co-expression of many combinations of cellulases and associated proteins. Here, we describe the development of a test platform based on Citrobacter freundii, a cellobiose-assimilating organism closely related to Escherichia coli. Standard E. coli cloning vectors worked well in Cit. freundii. Expression of cellulases CenA and Cex of Cellulomonas fimi in Cit. freundii gave recombinant strains which were able to grow at the expense of cellulosic filter paper or microcrystalline cellulose (Avicel) in a mineral medium supplemented with a small amount of yeast extract. Periodic physical agitation of the cultures was highly beneficial for growth at the expense of filter paper. This provides a test platform for the expression of combinations of genes encoding biomass-degrading enzymes to develop effective genetic cassettes for degradation of different biomass streams. SIGNIFICANCE AND IMPACT OF THE STUDY: Biofuels have been shown to be the best sustainable and alternative source of fuel to replace fossil fuels. Of the different types of feedstocks used for producing biofuels, lignocellulosic biomass is the most abundant. Converting this biomass to useful products has met with little success. Different approaches are being used and microbial platforms are the most promising and sustainable method. This study shows that Citrobacter freundii is a better test platform than Escherichia coli for testing various combinations of cellulases for the development of microbial systems for biomass conversion. PMID- 27617803 TI - A Novel Parkinson's Disease Drug Candidate with Potent Anti-neuroinflammatory Effects through the Src Signaling Pathway. AB - Numerous drug treatments are available for Parkinson's disease (PD), an age related neurodegenerative disease, but most cause serious side effects. Therefore, novel therapeutic strategies that halt disease progression and allow for long-term administration are urgently needed. Neuroinflammation critically contributes to the pathogenesis of PD. Here, we report the discovery and optimization of phloroglucinol derivatives, a novel class of anti neuroinflammatory compounds. Structural modifications of the hit compound 3 methyl-1-(2,4,6-trihydroxyphenyl)butan-1-one produced 43 derivatives, including a preclinical candidate (compound 21), that exhibited potent in vitro anti neuroinflammatory effects, good blood-brain barrier penetration, and desirable safety margins in mice at a median lethal dose (LD50) >5000 mg/kg. Its in vivo efficacy was demonstrated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- and MPTP/probenecid (prob)-induced subacute and chronic PD models, respectively, and alpha-synuclein transgenic mice. Mechanistic studies revealed neuroinflammation inhibition by targeting Src/phosphatase and tensin homologue deleted on chromosome 10 (PTEN)/Akt signaling might be promising. We highlighted the potential usefulness of phloroglucinol derivatives in PD treatment. PMID- 27617804 TI - Usefulness of Microfat Grafting in Patients With Repaired Cleft Lip. AB - In many patients, the volume of the upper lip is deficient after cleft lip repair operation. However, there is no well-established procedure to correct this volume deficiency. In the present study, the authors attempted to increase the overall three-dimensional volume of the upper lip in repaired cleft lip patients with upper lip volume deficiency through autogenous microfat grafting. Thirty patients with upper lip volume deficiency after cleft lip repair underwent fat grafting in the upper lip from November 2007 to March 2015. Among these patients, postoperative outcome was evaluated in 15 patients using 2 methods for the evaluation. One method involved measuring the change in the shape of lips using pre- and postoperative photographs, and the other involved investigating the levels of satisfaction with the surgical results by distributing a scoring questionnaire to patients, doctors, and the general public. The ratio of upper lip protrusion relative to the lower lip increased by 46.71% on average after operation, and the sum of the vermilion heights increased by 31.68% on average. In the survey of satisfaction levels, patients, plastic surgeons, and the general public gave mean scores of 3.80, 3.91, and 4.03, respectively. When volume deficiency of the upper lip is present in repaired cleft lip patients, correction using autogenous microfat grafting is believed to be effective. PMID- 27617805 TI - Basic Research and Clinical Application of Pterygoplatione Fossa Projection on Lateral Nasal Wall. AB - Infection, neoplasms, and tumor-like lesion in pterygoplatione fossa (PPF) are common in Chinese people. Owing to its deep anatomic location, surgery through this region is difficult. Maxillary sinus pathway is widely used, but the obvious disadvantage of destroying maxillary sinus even disfigurement cannot be avoided. This study provides a new method to locate PPF by choosing some landmarks situated at lateral wall of nasal cavity as reference points to obtain credible and detailed information for clinical management. The authors measured the location of anterior wall, posterior wall, and medial wall of PPF in the planes of middle nasal concha osseous extremity, inferior nasal concha osseous extremity, and middle nasal meatus. In addition, the authors measured the distance and the angle between the upper and lower bound of the PPF and the apertura sinus maxillaris. All PPF and landmarks of 196 patients were well demonstrated on computed tomographic angiography images. The new location method is stable and direct. As for the shape of PPF, the line connecting anterior wall in different planes is curve, convex backward, and concave frontward. Pterygoplatione fossa tapers gradually. The authors also found that with the traditional method, after entering the maxillary sinus, the needle should be inserted <26 mm when aimed at the upper bound and 30 mm in women and 31 mm in men when aimed at the lower bound. PMID- 27617809 TI - Efficacy of Standard Costochondral Grafting in Patients With Bilateral Craniofacial Microsomia. AB - Craniofacial microsomia remains the second most common craniofacial deformity after cleft lip and palate. Mandibular pathology has been classically scored from type I to type III by the modified Pruzansky-Kaban classification. The authors report a case of a 5-year-old patient with Goldenhar syndrome and bilateral type III craniofacial macrosomia. The patient had absence of bilateral glenoid fossas, condyles, coronoids, and rami as well as hypoplasia of the symphysis, parasymphysis, and mandibular body. Reconstruction was performed using 2 costochondral rib autografts to reconstruct a ramus and assist in the development of a neo-glenoid fossa at the cranial base. An additional portion of costal rib graft was used to augment the deficient symphysis. The patient was placed in class III occlusion postoperatively using maxillo-mandibular fixation screws and heavy elastics. The bone grafts healed without complications with no evidence of ankylosis, nonunion, or resorption to date. For the most severe forms of craniofacial microsomia, costochondral grafting remains an effective initial technique for lengthening the hypoplastic mandible and providing a foundation for future distraction. PMID- 27617816 TI - Parry-Romberg Syndrome on a Major French Revolution Leader: Mirabeau, 1791. PMID- 27617824 TI - Coronary Stenting to Treat Dyspnea in a Patient With Severe Lung Disease: A Teachable Moment. PMID- 27617823 TI - Using Hyperpolarized 129Xe MRI to Quantify the Pulmonary Ventilation Distribution. AB - RATIONALE AND OBJECTIVES: Ventilation heterogeneity is impossible to detect with spirometry. Alternatively, pulmonary ventilation can be imaged three dimensionally using inhaled 129Xe magnetic resonance imaging (MRI). To date, such images have been quantified primarily based on ventilation defects. Here, we introduce a robust means to transform 129Xe MRI scans such that the underlying ventilation distribution and its heterogeneity can be quantified. MATERIALS AND METHODS: Quantitative 129Xe ventilation MRI was conducted in 12 younger (24.7 +/- 5.2 years) and 10 older (62.2 +/- 7.2 years) healthy individuals, as well as in 9 younger (25.9 +/- 6.4 yrs) and 10 older (63.2 +/- 6.1 years) asthmatics. The younger healthy population was used to establish a reference ventilation distribution and thresholds for six intensity bins. These bins were used to display and quantify the ventilation defect region (VDR), the low ventilation region (LVR), and the high ventilation region (HVR). RESULTS: The ventilation distribution in young subjects was roughly Gaussian with a mean and standard deviation of 0.52 +/- 0.18, resulting in VDR = 2.1 +/- 1.3%, LVR = 15.6 +/- 5.4%, and HVR = 17.4 +/- 3.1%. Older healthy volunteers exhibited a significantly right skewed distribution (0.46 +/- 0.20, P = 0.034), resulting in significantly increased VDR (7.0 +/- 4.8%, P = 0.008) and LVR (24.5 +/- 11.5%, P = 0.025). In the asthmatics, VDR and LVR increased in the older population, and HVR was significantly reduced (13.5 +/- 4.6% vs 18.9 +/- 4.5%, P = 0.009). Quantitative 129Xe MRI also revealed altered ventilation heterogeneity in response to albuterol in two asthmatics with normal spirometry. CONCLUSIONS: Quantitative 129Xe MRI provides a robust and objective means to display and quantify the pulmonary ventilation distribution, even in subjects who have airway function impairment not appreciated by spirometry. PMID- 27617829 TI - Understanding Malnutrition of Tribal Children in India: The Role of Women's Empowerment. AB - Child malnutrition is considered to be the key risk factor for illness during adolescence and is responsible for about one-third of child deaths globally. Historically tribal communities have lagged behind the general population in terms of most socioeconomic aspects, and one such aspect is the nutritional status of children. The present study analyzes regional variations in child malnutrition and its association with women's empowerment in the tribal communities of India. The investigation is based on secondary data compiled from India's third National Family Health Survey (NFHS). Both bivariate and multivariate techniques were used to analyze data. We found a conditional inverse association between child malnutrition and women's empowerment in tribal communities. It is conditional in the sense that women's empowerment is effective when other factors supposed to influence nutritional status are proactive. Policy prescriptions are discussed. PMID- 27617830 TI - Electric Field Actuation of Tough Electroactive Hydrogels Cross-Linked by Functional Triblock Copolymer Micelles. AB - Multiresponsive polyelectrolyte hydrogels with extraordinary toughness have great potential in soft device applications. Previously we have demonstrated a series of tough and multiresponsive hydrogels by using multifunctional triblock copolymer (Pluronic F127 diacrylate, F127DA) micelles to cross-link cationic polyelectrolyte chains into 3D network. Herein, we further synthesize negatively charged hydrogels comprising 2-acrylamido-2-methyl propylsulfonic acid (AMPS) monomers by using F127DA micelles as cross-linkers. Similar to the positive nanomicelle (NM) hydrogels, the negative NM hydrogels exhibited a compressive strength up to 59 MPa with a fracture strain up to 98%, and tensile fracture strain higher than 2000%. These charged hydrogels were actuated by electric field when immersed in salt solutions. The effects of electrolyte concentration, electric field strength, and ionic monomer content on the electric actuation behavior of these electroactive hydrogels (EAHs) have been systematically investigated. It is concluded that the electroactive hydrogels show a fast actuation rate with a bending angle up to 87 degrees at 120 s and the bending angle was cyclically reversed upon changing bias direction without a large decrease. This study demonstrates that such tough and multiresponsive electroactive hydrogels may have great potential in sensors, actuators, switches, and artificial muscles. PMID- 27617831 TI - Human Perceptions Mirror Realities of Carnivore Attack Risk for Livestock: Implications for Mitigating Human-Carnivore Conflict. AB - Human-carnivore conflict is challenging to quantify because it is shaped by both the realities and people's perceptions of carnivore threats. Whether perceptions align with realities can have implications for conflict mitigation: misalignments can lead to heightened and indiscriminant persecution of carnivores whereas alignments can offer deeper insights into human-carnivore interactions. We applied a landscape-scale spatial analysis of livestock killed by tigers and leopards in India to model and map observed attack risk, and surveyed owners of livestock killed by tigers and leopards for their rankings of threats across habitats to map perceived attack risk. Observed tiger risk to livestock was greatest near dense forests and at moderate distances from human activity while leopard risk was greatest near open vegetation. People accurately perceived spatial differences between tiger and leopard hunting patterns, expected greater threat in areas with high values of observed risk for both carnivores. Owners' perception of threats largely did not depend on environmental conditions surrounding their village (spatial location, dominant land-use or observed carnivore risk). Surveys revealed that owners who previously lost livestock to carnivores used more livestock protection methods than those who had no prior losses, and that owners who had recently lost livestock for the first time expressed greater interest in changing their protection methods than those who experienced prior losses. Our findings suggest that in systems where realities and perceptions of carnivore risk align, conservation programs and policies can optimize conservation outcomes by (1) improving the effectiveness of livestock protection methods and (2) working with owners who have recently lost livestock and are most willing to invest effort in adapting protection strategies to mitigate human-carnivore conflict. PMID- 27617833 TI - Redescription of the Advertisement Call of Five Species of Thoropa (Anura, Cycloramphidae), Including Recordings of Rare and Endangered Species. AB - Frogs of the genus Thoropa comprise six endemic Brazilian species on the Eastern side of the country. Little is known about their natural history, especially about their acoustic communication. Therefore, aiming to provide an overview of their vocalizations, we analyzed and redescribed male advertisement calls of three living and two possibly extinct species. The smaller species, T. petropolitana and T. lutzi, produce simple calls (one single note) with a higher frequency range than the remaining larger ones. On the other hand, the larger species present complex calls, with more than one note: T. megatympanum calls have three notes, T. taophora calls have four notes, and T. miliaris calls varies from three to six notes. Population snout-vent length negatively correlated with peak of dominant frequency as expected. However, highlighted differences between two populations of T. lutzi, which could indicate need of further taxonomic evaluation of those lineages. Peculiar morphology, such as the absence of vocal sacs and slits, may have contributed to their call variation and highly banded frequency structure. If the observed population differences reflect species-level differences, T. lutzi may be classified as a critically endangered species, as T. petropolitana. Furthermore, we provided a suggestion to an unusual behavior in frogs: calling with the mouth open in the smaller species of the genus. PMID- 27617832 TI - Dexmedetomidine Injection during Strabismus Surgery Reduces Emergence Agitation without Increasing the Oculocardiac Reflex in Children: A Randomized Controlled Trial. AB - OBJECTIVE: Dexmedetomidine is known to reduce the incidence of emergence agitation, which is a common complication after inhalational anesthesia like sevoflurane or desflurane in children. However, the dose of dexmedetomidine used for this purpose is reported variously and the most effective dose is not known. In this study, we tried to find the most effective dose of dexmedetomidine to reduce the incidence of emergence agitation in children undergoing strabismus surgery without the complications like oculocardiac reflex (OCR) or postoperative vomiting. METHODS: We randomized 103 pediatric patients aged 2-6 years and undergoing elective strabismus surgery into four groups. Anesthesia was induced with sevoflurane and maintained with desflurane. At the start of induction, dexmedetomidine, delivered at 0.25, 0.5, or 1 MUg/kg, or saline was infused intravenously in the D0.25, D0.5, D1 groups, respectively. The primary outcome measure was the incidence of emergence agitation and the secondary outcome measure was the incidence of intraoperative OCR, postoperative vomiting, and desaturation events. RESULTS: The incidence of emergence agitation was 60, 48, 44, and 21% (P = 0.005) and the incidence of intraoperative OCR was 36, 36, 36, and 37% (P = 0.988) in the control, D0.25, D0.5, and D1 groups, respectively. And, postoperative vomiting rate and desaturation events were low in the all groups. CONCLUSION: Dexmedetomidine decreased the incidence of emergence agitation without increasing intraoperative oculocardiac reflex. Dexmedetomidine delivered at 1 MUg/kg was more effective at reducing emergence agitation than lower doses in children undergoing strabismus surgery under desflurane anesthesia. TRIAL REGISTRATION: Clinical Research Information Service KCT0000141. PMID- 27617834 TI - Characterization of Potent SMAC Mimetics that Sensitize Cancer Cells to TNF Family-Induced Apoptosis. AB - Members of the Inhibitor of APoptosis (IAP) protein family suppress apoptosis within tumor cells, particularly in the context of immune cell-mediated killing by the tumor necrosis factor (TNF) superfamily cytokines. Most IAPs are opposed endogenously by the second mitochondrial activator of caspases (SMAC), which binds to selected baculovirus IAP repeat (BIR) domains of IAPs to displace interacting proteins. The development of SMAC mimetics as novel anticancer drugs has gained impetus, with several agents now in human clinical trials. To further understand the cellular mechanisms of SMAC mimetics, we focused on IAP family members cIAP1 and cIAP2, which are recruited to TNF receptor complexes where they support cell survival through NF-kappaB activation while suppressing apoptosis by preventing caspase activation. We established fluorescence polarization (FP) assays for the BIR2 and BIR3 domains of human cIAP1 and cIAP2 using fluorochrome conjugated SMAC peptides as ligands. A library of SMAC mimetics was profiled using the FP assays to provide a unique structure activity relationship (SAR) analysis compared to previous assessments of binding to XIAP. Potent compounds displayed mean inhibitory binding constants (Ki) of 9 to 27 nM against the BIR3 domains of cIAP1 and cIAP2, respectively. Selected compounds were then characterized using cytotoxicity assays in which a cytokine-resistant human tumor cell line was sensitized to either TNF or lymphotoxin-alpha (LT-alpha). Cytotoxicity correlated closely with cIAP1 and cIAP2 BIR3 binding activity with the most potent compounds able to reduce cell viability by 50%. Further testing demonstrated that active compounds also inhibit RIP1 binding to BIR3 of cIAP1 and cIAP2 in vitro and reduce steady-state cIAP1 protein levels in cells. Altogether, these data inform the SAR for our SMAC mimetics with respect to cIAP1 and cIAP2, suggesting that these IAP family members play an important role in tumor cell resistance to cytotoxicity mediated by TNF and LT-alpha. PMID- 27617836 TI - Correction: Costs and Cost-Effectiveness of Hypertension Screening and Treatment in Adults with Hypertension in Rural Nigeria in the Context of a Health Insurance Program. AB - [This corrects the article DOI: 10.1371/journal.pone.0157925.]. PMID- 27617835 TI - Statistical Analysis of Tract-Tracing Experiments Demonstrates a Dense, Complex Cortical Network in the Mouse. AB - Anatomical tract tracing methods are the gold standard for estimating the weight of axonal connectivity between a pair of pre-defined brain regions. Large studies, comprising hundreds of experiments, have become feasible by automated methods. However, this comes at the cost of positive-mean noise making it difficult to detect weak connections, which are of particular interest as recent high resolution tract-tracing studies of the macaque have identified many more weak connections, adding up to greater connection density of cortical networks, than previously recognized. We propose a statistical framework that estimates connectivity weights and credibility intervals from multiple tract-tracing experiments. We model the observed signal as a log-normal distribution generated by a combination of tracer fluorescence and positive-mean noise, also accounting for injections into multiple regions. Using anterograde viral tract-tracing data provided by the Allen Institute for Brain Sciences, we estimate the connection density of the mouse intra-hemispheric cortical network to be 73% (95% credibility interval (CI): 71%, 75%); higher than previous estimates (40%). Inter hemispheric density was estimated to be 59% (95% CI: 54%, 62%). The weakest estimable connections (about 6 orders of magnitude weaker than the strongest connections) are likely to represent only one or a few axons. These extremely weak connections are topologically more random and longer distance than the strongest connections, which are topologically more clustered and shorter distance (spatially clustered). Weak links do not substantially contribute to the global topology of a weighted brain graph, but incrementally increased topological integration of a binary graph. The topology of weak anatomical connections in the mouse brain, rigorously estimable down to the biological limit of a single axon between cortical areas in these data, suggests that they might confer functional advantages for integrative information processing and/or they might represent a stochastic factor in the development of the mouse connectome. PMID- 27617837 TI - Perceived Symptom Experience in Head and Neck Cancer Patients with Lymphedema. AB - BACKGROUND: Lymphedema frequently develops as a long-term effect from cancer and/or its treatment, including head and neck cancer (HNC). There is a substantial lack of understanding regarding the symptoms and experiences related to head and neck lymphedema. OBJECTIVE: The objective of this study was to explore HNC patients' experiences of lymphedema, with emphasis on physical findings and associated symptom burden. DESIGN: This was a qualitative, descriptive study. A purposive sample of 20 HNC patients who completed lymphedema therapy participated in semistructured, face-to-face interviews. Thematic content analysis was utilized to assess data. RESULTS: Participants delineated the time when lymphedema onset presented and the sites of involvement. Most participants first noticed external or internal lymphedema/swelling within three months following either surgery or radiation therapy. Participants described a broad array of concurrent symptoms and functional deficits, including altered sensations, altered functions, neck-shoulder musculoskeletal/skin impairments, and psychosocial symptoms. DISCUSSION: HNC patients experienced multiple physical and psychosocial symptoms during the time they experienced lymphedema. CONCLUSIONS: Clinicians need to inquire about tissue swelling and associated symptoms early in the post-treatment period to initiate lymphedema management strategies in a timely manner and facilitate reduction of long-term symptom burden and functional deficits. PMID- 27617839 TI - Impact of Fatigue on Maintenance of Upright Posture: Dynamic Assessment of Sagittal Spinal Deformity Parameters After Walking 10 Minutes. AB - STUDY DESIGN: Retrospective analysis of prospectively collected data. OBJECTIVE: To assess global and regional spinal sagittal radiographic parameters in adults with loss of lumbar lordosis ("flatback") before and after walking 10 minutes. SUMMARY OF BACKGROUND DATA: While routine activities of daily living may exacerbate functional disability of spinal sagittal-plane deformity, there is limited understanding of how sagittal parameters and compensatory mechanisms are affected by activity. METHODS: Consecutive adults with "flatback" at a single institution who previously had full-length standing spinal radiographs before and after walking 10 minutes were reviewed. Changes in spinal deformity sagittal parameters before and after walking were evaluated for two groups: Compensated Sagittal Deformity ("Compensated": sagittal vertical axis [SVA] <=4 cm and pelvic tilt [PT] >20 degrees ) and Decompensated Sagittal Deformity ("Decompensated": SVA>4 cm and PT>20 degrees ). Intra-group radiographic comparisons were performed with paired Student t tests. RESULTS: One hundred fifty-seven patients (143 females, 14 males; average age 67.9 +/- 5.9 yr) met inclusion criteria. Initial average SVA was 1.7 +/- 1.2 cm for "Compensated" and 11.5 +/- 6.4 cm for "Decompensated." After walking 10 minutes, significant deteriorations in average SVA were observed for all "Decompensated" patients and 84.6% of "Compensated" patients. For both groups, this was accompanied by significant decreases in PT and LL and increases in PI-LL (P <0.01). Thoracic kyphosis increased after walking for only "Decompensated" (P <0.01). For "Compensated," the change in SVA was determined by decreases in PT and LL, while changes in SVA for "Decompensated" were correlated to worsening of all sagittal parameters. CONCLUSION: After walking, compensatory mechanisms to maintain sagittal balance in adults with spinal deformity are less pronounced than when the patient initially presents. This results in significant sagittal decompensation, irrespective of the initial SVA. As we postulate that loss of compensatory mechanisms is due to fatigue on pelvic and spinal extensor muscles, sagittal parameters can be re-evaluated with radiographs obtained after patients walk 10 minutes to unmask a hidden sagittal imbalance in compensated deformities. LEVEL OF EVIDENCE: 3. PMID- 27617843 TI - Synthesis of 2-Ethenylcyclopropyl Aryl Ketones via Intramolecular SN2-like Displacement of an Ester. AB - The efficient synthesis of trans-2-ethenylcyclopropyl aryl ketones via an intramolecular SN2-like displacement of an allylic ester is reported. A novel 1,5 acyl shift process is also observed that contributes to the product mixture. Theoretical calculations provide a rationale for the observed product ratio. PMID- 27617842 TI - Anticonvulsant effect of argan oil on pilocarpine model induced status epilepticus in wistar rats. AB - Argan oil (AO) is rich in oleic and linoleic acids, polyphenols, sterols, and tocopherols. This composition gives it numerous beneficial pharmacological effects such as hypolipemiant, hypotensive, and antiproliferative. Oxidative stress is a mechanism of cell death induced by seizures and status epilepticus (SE). This study aims at investigating AO effects on (i) latency to first seizure, seizure severity, weight loss, mortality rate, (ii) lipid peroxidation level, nitrite level, and catalase activity in the hippocampus after SE induced by pilocarpine (PC). Wistar rats (1-month old) were daily administered by oral gavage with AO (1 ml/100 g/day) or with NaCl 0.9% during 2 months before receiving PC (400 mg/kg). After the PC injection, all groups were observed for 24 h. The catalase activity, the lipid peroxidation, and nitrite concentrations were measured using spectrophotometric methods. AO pretreatment increased the latency to first seizures, decreased the weight loss, and reduced mortality rate after SE. AO pretreatment produces significant decrease of the lipid peroxidation and nitrite levels. On the contrary, AO increased the catalase activity in rat hippocampus after seizures. For the first time, our results suggest that AO pretreatment is capable of attenuating seizure severity and oxidative stress in the hippocampus of Wistar rats. This indicates that AO may exhibit a neuroprotection against the temporal lobe epilepsy. Further investigations are in progress to confirm this pharmacological property. PMID- 27617840 TI - Clinical and Biological Risk Factors for Neuropsychological Impairment in Alcohol Use Disorder. AB - The effects of alcoholism on cognitive and motor functioning are heterogeneous. While the role of some factors (patterns of alcohol consumption, eating habits or associated liver disease) has been hypothesized, the origins of this heterogeneity remain difficult to establish. The goals of the present study were thus to identify the clinical and biological risk factors for alcohol-related neuropsychological impairments and to determine the threshold beyond which these risk factors can be considered significant. Thirty alcoholic patients and 15 healthy controls had a blood test and underwent a neuropsychological examination. Alcohol severity measures, and liver, thiamine and malnutrition variables, were included in logistic regression models to determine the risk factors for cognitive and motor impairments (executive functions, visuospatial abilities, verbal episodic memory, ataxia), as well as those related to the severity of patients' overall neuropsychological profile (moderate or severe impairments). Liver fibrosis was found to be a risk factor for executive impairments and also for ataxia, when it was associated with long-term alcohol misuse and symptoms of withdrawal. Altered thiamine metabolism was solely predictive of verbal episodic memory impairments. This combination of biological abnormalities was associated with a profile of moderate neuropsychological impairments. Malnutrition was associated with a profile of more severe impairments. Malnutrition, altered liver function and thiamine metabolism explain, at least partially, the heterogeneity of alcohol-related neuropsychological impairments. Our findings could allow clinicians to identify patients at particular risk of severe neuropsychological impairments before the onset of irreversible and debilitating neurological complications. PMID- 27617844 TI - Neuropathic pain following traumatic spinal cord injury: Models, measurement, and mechanisms. AB - Neuropathic pain following spinal cord injury (SCI) is notoriously difficult to treat and is a high priority for many in the SCI population. Resolving this issue requires animal models fidelic to the clinical situation in terms of injury mechanism and pain phenotype. This Review discusses the means by which neuropathic pain has been induced and measured in experimental SCI and compares these with human outcomes, showing that there is a substantial disconnection between experimental investigations and clinical findings in a number of features. Clinical injury level is predominantly cervical, whereas injury in the laboratory is modeled mainly at the thoracic cord. Neuropathic pain is primarily spontaneous or tonic in people with SCI (with a relatively smaller incidence of allodynia), but measures of evoked responses (to thermal and mechanical stimuli) are almost exclusively used in animals. There is even the question of whether pain per se has been under investigation in most experimental SCI studies rather than simply enhanced reflex activity with no affective component. This Review also summarizes some of the problems related to clinical assessment of neuropathic pain and how advanced imaging techniques may circumvent a lack of patient/clinician objectivity and discusses possible etiologies of neuropathic pain following SCI based on evidence from both clinical studies and animal models, with examples of cellular and molecular changes drawn from the entire neuraxis from primary afferent terminals to cortical sensory and affective centers. (c) 2016 Wiley Periodicals, Inc. PMID- 27617845 TI - Leveraging Industry-Academia Collaborations in Adaptive Biomedical Innovation. AB - Despite the rapid pace of biomedical innovation, research and development (R&D) productivity in the pharmaceutical industry has not improved broadly. Increasingly, firms need to leverage new approaches to product development and commercial execution, while maintaining adaptability to rapid changes in the marketplace and in biomedical science. Firms are also seeking ways to capture some of the talent, infrastructure, and innovation that depends on federal R&D investment. As a result, a major transition to external innovation is taking place across the industry. One example of these external innovation initiatives is the Sanofi-MIT Partnership, which provided seed funding to MIT investigators to develop novel solutions and approaches in areas of interest to Sanofi. These projects were highly collaborative, with information and materials flowing both ways. The relatively small amount of funding and short time frame of the awards built an adaptable and flexible process to advance translational science. PMID- 27617846 TI - Activity Profiles and the Associations With Weight Status in Population Studies of Young Children: Are There Gender Differences? AB - PURPOSE: Profiling activity behaviors in young children is important to understand changes in weight status over time. The purpose of this study is to identify activity profiles from self- and parental-reported Physical Activity (PA) and Sedentary Behavior (SB) variables by gender, and determine if the identified profiles are predictive of weight change from age 9-13 years. METHODS: Cluster analysis was used to generate activity profiles for the National Longitudinal Study of 8570 9-year-old children (Growing Up in Ireland). RESULTS: 5.4% of boys were found to be obese. Four cohesive activity profiles were identified for boys, with 7.3% of boys in the least active group identified as obese compared with 4.1% in the most active group. The odds of a normal weight 9 year-old boy in the least active profile becoming overweight or obese at age 13 were over twice those in most active profile (OR = 2.5, 95% CI: 1.9, 3.5). No coherent activity profiles were identified for girls. CONCLUSIONS: This study suggests that self- and parental-reported data can identify meaningful activity profiles for boys, which are predictive of weight changes over time. Future research should consider potential gender differences in self- and parental reported PA and SB variables. PMID- 27617847 TI - Automatic Detection of Pitching and Throwing Events in Baseball With Inertial Measurement Sensors. AB - PURPOSE: Throwing loads are known to be closely related to injury risk. However, for logistic reasons, typically only pitchers have their throws counted, and then only during innings. Accordingly, all other throws made are not counted, so estimates of throws made by players may be inaccurately recorded and underreported. A potential solution to this is the use of wearable microtechnology to automatically detect, quantify, and report pitch counts in baseball. This study investigated the accuracy of detection of baseball pitching and throwing in both practice and competition using a commercially available wearable microtechnology unit. METHODS: Seventeen elite youth baseball players (mean +/- SD age 16.5 +/- 0.8 y, height 184.1 +/- 5.5 cm, mass 78.3 +/- 7.7 kg) participated in this study. Participants performed pitching, fielding, and throwing during practice and competition while wearing a microtechnology unit. Sensitivity and specificity of a pitching and throwing algorithm were determined by comparing automatic measures (ie, microtechnology unit) with direct measures (ie, manually recorded pitching counts). RESULTS: The pitching and throwing algorithm was sensitive during both practice (100%) and competition (100%). Specificity was poorer during both practice (79.8%) and competition (74.4%). CONCLUSIONS: These findings demonstrate that the microtechnology unit is sensitive to detect pitching and throwing events, but further development of the pitching algorithm is required to accurately and consistently quantify throwing loads using microtechnology. PMID- 27617849 TI - Substrate-Assisted Catalysis in Polyketide Reduction Proceeds via a Phenolate Intermediate. AB - SimC7 is a polyketide ketoreductase involved in biosynthesis of the angucyclinone moiety of the gyrase inhibitor simocyclinone D8 (SD8). SimC7, which belongs to the short-chain dehydrogenase/reductase (SDR) superfamily, catalyzes reduction of the C-7 carbonyl of the angucyclinone, and the resulting hydroxyl is essential for antibiotic activity. SimC7 shares little sequence similarity with characterized ketoreductases, suggesting it might have a distinct mechanism. To investigate this possibility, we determined the structures of SimC7 alone, with NADP(+), and with NADP(+) and the substrate 7-oxo-SD8. These structures show that SimC7 is distinct from previously characterized polyketide ketoreductases, lacking the conserved catalytic triad, including the active-site tyrosine that acts as central acid-base catalyst in canonical SDR proteins. Taken together with functional analyses of active-site mutants, our data suggest that SimC7 catalyzes a substrate-assisted, two-step reaction for reduction of the C-7 carbonyl group involving intramolecular transfer of a substrate-derived proton to generate a phenolate intermediate. PMID- 27617850 TI - Selective Covalent Targeting of Anti-Apoptotic BFL-1 by Cysteine-Reactive Stapled Peptide Inhibitors. AB - Anti-apoptotic BCL-2 family proteins block cell death by trapping the critical alpha-helical BH3 domains of pro-apoptotic members in a surface groove. Cancer cells hijack this survival mechanism by overexpressing a spectrum of anti apoptotic members, mounting formidable apoptotic blockades that resist chemotherapeutic treatment. Drugging the BH3-binding pockets of anti-apoptotic proteins has become a highest-priority goal, fueled by the clinical success of ABT-199, a selective BCL-2 inhibitor, in reactivating apoptosis in BCL-2 dependent cancers. BFL-1 is a BCL-2 homolog implicated in melanoma, lymphoma, and other cancers, and remains undrugged. A natural juxtaposition of two unique cysteines at the binding interface of the NOXA BH3 helix and BFL-1 pocket informed the development of stapled BH3 peptides bearing acrylamide warheads to irreversibly inhibit BFL-1 by covalent targeting. Given the frequent proximity of native cysteines to regulatory binding surfaces, covalent stapled peptide inhibitors provide a new therapeutic strategy for targeting pathologic protein interactions. PMID- 27617852 TI - National Quality Forum Colon Cancer Quality Metric Performance: How Are Hospitals Measuring Up? AB - OBJECTIVE: To evaluate the impact of care at high-performing hospitals on the National Quality Forum (NQF) colon cancer metrics. BACKGROUND: The NQF endorses evaluating >=12 lymph nodes (LNs), adjuvant chemotherapy (AC) for stage III patients, and AC within 4 months of diagnosis as colon cancer quality indicators. Data on hospital-level metric performance and the association with survival are unclear. METHODS: Retrospective cohort study of 218,186 patients with resected stage I to III colon cancer in the National Cancer Data Base (2004-2012). High performing hospitals (>75% achievement) were identified by the proportion of patients achieving each measure. The association between hospital performance and survival was evaluated using Cox shared frailty modeling. RESULTS: Only hospital LN performance improved (15.8% in 2004 vs 80.7% in 2012; trend test, P < 0.001), with 45.9% of hospitals performing well on all 3 measures concurrently in the most recent study year. Overall, 5-year survival was 75.0%, 72.3%, 72.5%, and 69.5% for those treated at hospitals with high performance on 3, 2, 1, and 0 metrics, respectively (log-rank, P < 0.001). Care at hospitals with high metric performance was associated with lower risk of death in a dose-response fashion [0 metrics, reference; 1, hazard ratio (HR) 0.96 (0.89-1.03); 2, HR 0.92 (0.87 0.98); 3, HR 0.85 (0.80-0.90); 2 vs 1, HR 0.96 (0.91-1.01); 3 vs 1, HR 0.89 (0.84 0.93); 3 vs 2, HR 0.95 (0.89-0.95)]. Performance on metrics in combination was associated with lower risk of death [LN + AC, HR 0.86 (0.78-0.95); AC + timely AC, HR 0.92 (0.87-0.98); LN + AC + timely AC, HR 0.85 (0.80-0.90)], whereas individual measures were not [LN, HR 0.95 (0.88-1.04); AC, HR 0.95 (0.87-1.05)]. CONCLUSIONS: Less than half of hospitals perform well on these NQF colon cancer metrics concurrently, and high performance on individual measures is not associated with improved survival. Quality improvement efforts should shift focus from individual measures to defining composite measures encompassing the overall multimodal care pathway and capturing successful transitions from one care modality to another. PMID- 27617851 TI - Chemical Targeting of a G-Quadruplex RNA in the Ebola Virus L Gene. AB - In the present study, our bioinformatics analysis first reveals the existence of a conserved guanine-rich sequence within the Zaire ebolavirus L gene. Using various methods, we show that this sequence tends to fold into G-quadruplex RNA. TMPyP4 treatment evidently inhibits L gene expression at the RNA level. Moreover, the mini-replicon assay demonstrates that TMPyP4 effectively inhibits the artificial Zaire ebolavirus mini-genome and is a more potent inhibitor than ribavirin. Although TMPyP4 treatment reduced the replication of the mutant mini genome when G-quadruplex formation was abolished in the L gene, its inhibitory effect was significantly alleviated compared with wild-type. Our findings thus provide the first evidence that G-quadruplex RNA is present in a negative-sense RNA virus. Finally, G-quadruplex RNA stabilization may represent a new therapeutic strategy against Ebola virus disease. PMID- 27617854 TI - Reply to Letter: "Long-term Survival Based on the Surgical Approach to Lobectomy for Clinical Stage I Nonsmall Cell Lung Cancer: Comparison of Robotic, Video assisted Thoracic Surgery, and Thoracotomy Lobectomy". PMID- 27617853 TI - Living or Brain-dead Donor Liver Transplantation for Hepatocellular Carcinoma: A Multicenter, Western, Intent-to-treat Cohort Study. AB - OBJECTIVE: An intent-to-treat analysis of overall survival (ITT-OS) of cirrhotic patients with hepatocellular carcinoma (HCC) listed for living donor liver transplantation (LDLT) or brain-dead donor liver transplantation (BDLT) across 5 French liver transplant (LT) centers. BACKGROUND: Comparisons of HCC outcomes after LDLT and BDLT measured from time of transplantation have yielded conflicting results. METHODS: Records from 861 cirrhotic patients with HCC consecutively listed for either LDLT (n = 79) or BDLT (n = 782) from 2000 to 2009 were analyzed for ITT-OS using a Cox model; and tumor recurrence using 2 competitive risk models. RESULTS: Tumor staging was similar between groups. In total, 162 patients dropped out (20.7%), all from Group BDLT (P < 0.0001). The postoperative mortality rate and the retransplantation rate were similar between LDLT and BDLT. At 5 years, no statistically significant difference was found in ITT-OS between LDLT and BDLT groups (73.2% vs 66.7%; P = 0.062). LDLT waitlist inclusion (hazard ratio: 0.61 (0.39-0.96); P = 0.034) and a time-of-listing MELD score >= 25 (hazard ratio: 1.93 (1.15-3.26); P = 0.014) were independent predictors of ITT-OS. Similar 5-year post-LT OS rates (73.2% and 73.0% for Group LDLT and Group BDLT, respectively; P = 0.407) and HCC recurrence rates (10.9% and 11.2% for Group LDLT and Group BDLT, respectively; P = 0.753) were found. Upon explant analysis, tumors exceeding the Milan criteria, macroscopic vascular invasion, and AFP score>2 were independent predictors of recurrence, whereas LT type was not. CONCLUSIONS: LDLT improves ITT-OS, and it is not a risk factor for tumor recurrence. Therefore, LDLT and BDLT should be equally encouraged in countries where both are available. PMID- 27617855 TI - Prognostic Significant or Not? The Positive Circumferential Resection Margin in Esophageal Cancer: Impact on Local Recurrence and Overall Survival in Patients Without Neoadjuvant Treatment. AB - OBJECTIVE: The aim of this study is to investigate the impact of the circumferential resection margin (CRM) in esophageal cancer on survival and recurrence in patients without pretreatment. BACKGROUND: Whereas the infiltration of the proximal or distal resection margin is associated with poor survival and higher recurrence, studies looking at the role of the circumferential resection margin on survival and local recurrence after esophagectomy are conflicting. METHODS: Influence of CRM infiltration according to the College of American Pathologists (CAP) and Royal College of Pathologists (RCP) on long-term survival of 180 patients with resected pT3 tumors and without neoadjuvant therapy was analyzed. RESULTS: A positive CRM was found in 76 (42.4%) patients according to RCP and 44 (24.4%) patients according to CAP. The CRM status had neither according to CAP nor according to RCP a significant impact on overall survival (P = 0.317 and 0.655, respectively), local recurrence (P = 0.716 and 0.900, respectively), or distant tumor relapse (P = 0.303 and 0.471, respectively).Lymphatic tumor spread found in 129 (71.7%) patients was an independent prognosticator (P = 0.002). In 137 (76.1%) patients who had a transthoracic esophagectomy a CRM infiltration was significantly lower according to CAP compared with 43 (23.9%) patients who had a transhiatal esophagectomy (P = 0.026). CONCLUSIONS: CRM was found to have no impact on survival and recurrence in esophageal cancer. Therefore, the possible impact of neoadjuvant pretreatment in locally advanced tumors should be considered with caution in terms of an improved resectability. PMID- 27617856 TI - The Risk of Adverse Pregnancy Outcomes Following Nonobstetric Surgery During Pregnancy: Estimates From a Retrospective Cohort Study of 6.5 Million Pregnancies. AB - OBJECTIVE: The aim of this study was to estimate the risk of adverse birth outcomes for women who underwent nonobstetric surgery during pregnancy compared with those who did not. BACKGROUND: Previous research suggests that nonobstetric surgery occurs during 1% to 2% of pregnancies. However, there is limited evidence quantifying risks to the mother or pregnancy of such surgery. METHODS: We examined maternity admissions using hospital administrative data collected between April 1, 2002, and March 31, 2012, and identified pregnancies wherein nonobstetric surgery occurred. We used logistic regression models to determine the adjusted relative risk, attributable risk, and number needed to harm of nonobstetric surgical procedures for adverse birth outcomes. RESULTS: We identified 6,486,280 pregnancies. In 47,628 of these pregnancies, nonobstetric surgery had occurred. We found that nonobstetric surgery during pregnancy was associated with a higher risk of adverse birth outcomes, although the attributable risk was generally low. We estimated that every 287 surgical operations were associated with 1 additional stillbirth, every 31 operations associated with 1 additional preterm delivery, every 39 operations associated with 1 additional low birth weight baby, every 25 operations associated with 1 additional caesarean section, and every 50 operations associated with 1 additional long inpatient stay. CONCLUSIONS: Although we have no means of disentangling the effect of the surgery from the effect of the underlying condition, we found that the risk associated with nonobstetric surgery was relatively low, confirming that surgical procedures during pregnancy are generally safe. We believe that our findings improve upon previous research, and are useful reference points for any discussion of risk with prospective patients. PMID- 27617857 TI - The postdoctoral apprenticeship. AB - Much has been written already about whether the scientific machine is churning out too many PhDs and postdocs when there are a limited number of academic jobs and the competition for funding and space in competitive journals is intense. But gratifyingly, there exists a vast array of other scientific careers. We need to mentor and advise trainees about the diverse and rewarding professional opportunities that are available beyond the postdoctoral apprenticeship period. PMID- 27617858 TI - Aging promotes acquisition of naive-like CD8+ memory T cell traits and enhanced functionalities. AB - Protective T cell memory is an acquired trait that is contingent upon the preservation of its constituents and therefore vulnerable to the potentially deleterious effects of organismal aging. Here, however, we have found that long term T cell memory in a natural murine host-pathogen system can substantially improve over time. Comprehensive molecular, phenotypic, and functional profiling of aging antiviral CD8+ memory T cells (CD8+ TM) revealed a pervasive remodeling process that promotes the gradual acquisition of distinct molecular signatures, of increasingly homogeneous phenotypes, and of diversified functionalities that combine to confer a CD8+ TM-autonomous capacity for enhanced recall responses and immune protection. Notably, the process of CD8+ TM aging is characterized by a progressive harmonization of memory and naive T cell traits, is broadly amenable to experimental acceleration or retardation, and serves as a constitutional component for the "rebound model" of memory T cell maturation. By casting CD8+ TM populations within the temporal framework of their slowly evolving properties, this model establishes a simple ontogenetic perspective on the principal organization of CD8+ T cell memory that may directly inform the development of improved diagnostic, prophylactic, and therapeutic modalities. PMID- 27617859 TI - Optogenetic defibrillation terminates ventricular arrhythmia in mouse hearts and human simulations. AB - Ventricular arrhythmias are among the most severe complications of heart disease and can result in sudden cardiac death. Patients at risk currently receive implantable defibrillators that deliver electrical shocks to terminate arrhythmias on demand. However, strong electrical shocks can damage the heart and cause severe pain. Therefore, we have tested optogenetic defibrillation using expression of the light-sensitive channel channelrhodopsin-2 (ChR2) in cardiac tissue. Epicardial illumination effectively terminated ventricular arrhythmias in hearts from transgenic mice and from WT mice after adeno-associated virus-based gene transfer of ChR2. We also explored optogenetic defibrillation for human hearts, taking advantage of a recently developed, clinically validated in silico approach for simulating infarct-related ventricular tachycardia (VT). Our analysis revealed that illumination with red light effectively terminates VT in diseased, ChR2-expressing human hearts. Mechanistically, we determined that the observed VT termination is due to ChR2-mediated transmural depolarization of the myocardium, which causes a block of voltage-dependent Na+ channels throughout the myocardial wall and interrupts wavefront propagation into illuminated tissue. Thus, our results demonstrate that optogenetic defibrillation is highly effective in the mouse heart and could potentially be translated into humans to achieve nondamaging and pain-free termination of ventricular arrhythmia. PMID- 27617860 TI - Interruption of progerin-lamin A/C binding ameliorates Hutchinson-Gilford progeria syndrome phenotype. AB - Hutchinson-Gilford progeria syndrome (HGPS) is a rare autosomal dominant genetic disease that is caused by a silent mutation of the LMNA gene encoding lamins A and C (lamin A/C). The G608G mutation generates a more accessible splicing donor site than does WT and produces an alternatively spliced product of LMNA called progerin, which is also expressed in normal aged cells. In this study, we determined that progerin binds directly to lamin A/C and induces profound nuclear aberrations. Given this observation, we performed a random screening of a chemical library and identified 3 compounds (JH1, JH4, and JH13) that efficiently block progerin-lamin A/C binding. These 3 chemicals, particularly JH4, alleviated nuclear deformation and reversed senescence markers characteristic of HGPS cells, including growth arrest and senescence-associated beta-gal (SA-beta-gal) activity. We then used microarray-based analysis to demonstrate that JH4 is able to rescue defects of cell-cycle progression in both HGPS and aged cells. Furthermore, administration of JH4 to LmnaG609G/G609G-mutant mice, which phenocopy human HGPS, resulted in a marked improvement of several progeria phenotypes and an extended lifespan. Together, these findings indicate that specific inhibitors with the ability to block pathological progerin-lamin A/C binding may represent a promising strategy for improving lifespan and health in both HGPS and normal aging. PMID- 27617861 TI - NLRC4 suppresses melanoma tumor progression independently of inflammasome activation. AB - Members of the NLR family can assemble inflammasome complexes with the adaptor protein ASC and caspase-1 that result in the activation of caspase-1 and the release of IL-1beta and IL-18. Although the NLRC4 inflammasome is known to have a protective role in tumorigenesis, there is an increased appreciation for the inflammasome-independent actions of NLRC4. Here, we utilized a syngeneic subcutaneous murine model of B16F10 melanoma to explore the role of NLRC4 in tumor suppression. We found that NLRC4-deficient mice exhibited enhanced tumor growth that was independent of the inflammasome components ASC and caspase-1. Nlrc4 expression was critical for cytokine and chemokine production in tumor associated macrophages and was necessary for the generation of protective IFN gamma-producing CD4+ and CD8+ T cells. Tumor progression was diminished when WT or caspase-1-deficient, but not NLRC4-deficient, macrophages were coinjected with B16F10 tumor cells in NLRC4-deficient mice. Finally, examination of human primary melanomas revealed the extensive presence of NLRC4+ tumor-associated macrophages. In contrast, there was a paucity of NLRC4+ tumor-associated macrophages observed in human metastatic melanoma, supporting the concept that NLRC4 expression controls tumor growth. These results reveal a critical role for NLRC4 in suppressing tumor growth in an inflammasome-independent manner. PMID- 27617862 TI - COUP-TFII regulates satellite cell function and muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is a severe and progressive muscle-wasting disease caused by mutations in the dystrophin gene. Although dystrophin deficiency in myofiber triggers the disease's pathological changes, the degree of satellite cell (SC) dysfunction defines disease progression. Here, we have identified chicken ovalbumin upstream promoter-transcription factor II (COUP TFII) hyperactivity as a contributing factor underlying muscular dystrophy in a dystrophin-deficient murine model of DMD. Ectopic expression of COUP-TFII in murine SCs led to Duchenne-like dystrophy in the muscles of control animals and exacerbated degenerative myopathies in dystrophin-deficient mice. COUP-TFII overexpressing mice exhibited regenerative failure that was attributed to deficient SC proliferation and myoblast fusion. Mechanistically, we determined that COUP-TFII coordinated a regenerative program through combined regulation of multiple promyogenic factors. Furthermore, inhibition of COUP-TFII preserved SC function and counteracted the muscle weakness associated with Duchenne-like dystrophy in the murine model, suggesting that targeting COUP-TFII is a potential treatment for DMD. Together, our findings reveal a regulatory role of COUP-TFII in the development of muscular dystrophy and open up a potential therapeutic opportunity for managing disease progression in patients with DMD. PMID- 27617864 TI - Imaging Energy Transfer in Pt-Decorated Au Nanoprisms via Electron Energy-Loss Spectroscopy. AB - Driven by the desire to understand energy transfer between plasmonic and catalytic metals for applications such as plasmon-mediated catalysis, we examine the spatially resolved electron energy-loss spectra (EELS) of both pure Au nanoprisms and Pt-decorated Au nanoprisms. The EEL spectra and the resulting surface-plasmon mode maps reveal detailed near-field information on the coupling and energy transfer in these systems, thereby elucidating the underlying mechanism of plasmon-driven chemical catalysis in mixed-metal nanostructures. Through a combination of experiment and theory we demonstrate that although the location of the Pt decoration greatly influences the plasmons of the nanoprism, simple spatial proximity is not enough to induce significant energy transfer from the Au to the Pt. What matters more is the spectral overlap between the intrinsic plasmon resonances of the Au nanoprism and Pt decoration, which can be tuned by changing the composition or morphology of either component. PMID- 27617863 TI - ABC transporters and NR4A1 identify a quiescent subset of tissue-resident memory T cells. AB - Immune surveillance in tissues is mediated by a long-lived subset of tissue resident memory T cells (Trm cells). A putative subset of tissue-resident long lived stem cells is characterized by the ability to efflux Hoechst dyes and is referred to as side population (SP) cells. Here, we have characterized a subset of SP T cells (Tsp cells) that exhibit a quiescent (G0) phenotype in humans and mice. Human Trm cells in the gut and BM were enriched in Tsp cells that were predominantly in the G0 stage of the cell cycle. Moreover, in histone 2B-GFP mice, the 2B-GFP label was retained in Tsp cells, indicative of a slow-cycling phenotype. Human Tsp cells displayed a distinct gene-expression profile that was enriched for genes overexpressed in Trm cells. In mice, proteins encoded by Tsp signature genes, including nuclear receptor subfamily 4 group A member 1 (NR4A1) and ATP-binding cassette (ABC) transporters, influenced the function and differentiation of Trm cells. Responses to adoptive transfer of human Tsp cells into immune-deficient mice and plerixafor therapy suggested that human Tsp cell mobilization could be manipulated as a potential cellular therapy. These data identify a distinct subset of human T cells with a quiescent/slow-cycling phenotype, propensity for tissue enrichment, and potential to mobilize into circulation, which may be harnessed for adoptive cellular therapy. PMID- 27617865 TI - Parkinson's disease in Jordan: Barriers and motivators to exercise. AB - BACKGROUND: Perceived barriers to engaging in exercise in people with Parkinson's disease (PD) are becoming more defined in countries such as the UK and the US. This, however, may vary by culture and environment. This study aimed to explore the perceptions of exercise and barriers that may affect participation in people with PD from Jordan. METHODS: Two focus groups and seven individual interviews were conducted with people with PD. Additionally, individual interviews were conducted with two neurologists. Conversations were digitally recorded and transcribed. Transcripts were analyzed using thematic analysis and validated via researcher triangulation and peer checking. RESULTS: Most of the PD participants lacked previous participation in any disease-specific exercises. Several barriers were perceived by PD participants for such lack of participation. Barriers included difficulty of diagnosis, lack of informational support provided by neurologists, lack of referral to physiotherapy services, disease-specific issues, and setting-related issues. Neurologists indicated a number of barriers in counseling their PD patients on exercise including lack of time and lack of health system resources. Motivators to participate in future exercise included outcome expectations and family support. CONCLUSIONS: Findings of the study shed light into large areas of unmet needs of supporting exercise and physiotherapy for people with PD in developing countries as per Jordan. For better patient outcomes, findings of the study suggest that it is crucial to raise awareness among all PD-related stakeholders on the benefits of early referrals to physiotherapy and early engagement in exercise programs. PMID- 27617866 TI - Size effects of solvent molecules on the phase behavior and effective interaction of colloidal systems with the bridging attraction. AB - There has been much recent research interest towards understanding the phase behavior of colloidal systems interacting with a bridging attraction, where the small solvent particles and large solute colloidal particles can be reversibly associated with each other. These systems show interesting phase behavior compared to the more widely studied depletion attraction systems. Here, we use Baxter's two-component sticky hard sphere model with a Percus-Yevick closure to solve the Ornstein-Zernike equation and study the size effect on colloidal systems with bridging attractions. The spinodal decomposition regions, percolation transition boundaries and binodal regions are systematically investigated as a function of the relative size of the small solvent and large solute particles as well as the attraction strength between the small and large particles. In the phase space determined by the concentrations of small and large particles, the spinodal and binodal regions form isolated islands. The locations and shapes of the spinodal and binodal regions sensitively depend on the relative size of the small and large particles and the attraction strength between them. The percolation region shrinks by decreasing the size ratio, while the binodal region slightly expands with the decrease of the size ratio. Our results are very important in understanding the phase behavior for a bridging attraction colloidal system, a model system that provides insight into oppositely charged colloidal systems, protein phase behavior, and colloidal gelation mechanisms. PMID- 27617867 TI - A novel infusion-drainage device to assess lower urinary tract function in neuro imaging. AB - OBJECTIVE: To evaluate the applicability and precision of a novel infusion drainage device (IDD) for standardized filling paradigms in neuro-urology and functional magnetic resonance imaging (fMRI) studies of lower urinary tract (LUT) function/dysfunction. SUBJECTS/PATIENTS AND METHODS: The IDD is based on electrohydrostatic actuation which was previously proven feasible in a prototype setup. The current design includes hydraulic cylinders and a motorized slider to provide force and motion. Methodological aspects have been assessed in a technical application laboratory as well as in healthy subjects (n=33) and patients with LUT dysfunction (n=3) undergoing fMRI during bladder stimulation. After catheterization, the bladder was pre-filled until a persistent desire to void was reported by each subject. The scan paradigm comprised automated, repetitive bladder filling and withdrawal of 100 mL body warm (37 degrees C) saline, interleaved with rest and sensation rating. Neuroimaging data were analysed using Statistical Parametric Mapping version 12 (SMP12). RESULTS: Volume delivery accuracy was between 99.1+/-1.2% and 99.9+/-0.2%, for different flow rates and volumes. Magnetic resonance (MR) compatibility was demonstrated by a small decrease in signal-to-noise ratio (SNR), i.e. 1.13% for anatomical and 0.54% for functional scans, and a decrease of 1.76% for time-variant SNR. Automated, repetitive bladder-filling elicited robust (P = 0.05, family-wise error corrected) brain activity in areas previously reported to be involved in supraspinal LUT control. There was a high synchronism between the LUT stimulation and the blood oxygenation level-dependent (BOLD) signal changes in such areas. CONCLUSION: We were able to develop an MR-compatible and MR-synchronized IDD to routinely stimulate the LUT during fMRI in a standardized manner. The device provides LUT stimulation at high system accuracy resulting in significant supraspinal BOLD signal changes in interoceptive and LUT control areas in synchronicity to the applied stimuli. The IDD is commercially available, portable and multi-configurable. Such a device may help to improve precision and standardization of LUT tasks in neuro-imaging studies on supraspinal LUT control, and may therefore facilitate multi-site studies and comparability between different LUT investigations in the future. PMID- 27617868 TI - Predictability and Vector Analysis of Laser In Situ Keratomileusis for Residual Errors in Eyes Implanted With Different Multifocal Intraocular Lenses. AB - PURPOSE: To investigate potential differences in predictability, efficacy, and safety of corneal excimer laser to correct residual myopia, hyperopia, and astigmatism in eyes previously implanted with multifocal intraocular lenses using distinct optical surfaces and platforms for multifocality. METHODS: This prospective comparative study included 37 eyes submitted to laser in situ keratomileusis correction for residual errors after implantation of either an apodized diffractive-refractive (Restor) or a full-diffractive (Tecnis) multifocal intraocular lens. Data analysis included investigation of predictability, efficacy, and safety of excimer laser surgery to correct residual errors. A double-angle plot, using vector analysis, was also created to evaluate predictability of astigmatism correction. RESULTS: At 6-month follow-up, statistical analyses revealed a significant improvement when comparing preoperative (0.51 +/- 0.25 and 0.44 +/- 0.18) and postoperative values (0.17 +/- 0.10 and 0.09 +/- 0.07) of uncorrected distance visual acuity (P < 0.0001 and <0.0001), preoperative (0.92 +/- 0.61 and 1.02 +/- 0.45) and postoperative values (0.33 +/- 0.23 and 0.19 +/- 0.17) of manifest refractive spherical equivalent (P = 0.0006 and <0.0001), and preoperative (-1.08 +/- 0.70 and -0.65 +/- 0.42) and postoperative values (-0.25 +/- 0.28 and -0.14 +/- 0.21) of astigmatism (P < 0.0001 and <0.0001) in eyes implanted with Restor and Tecnis, respectively. Vector analysis revealed a predictable correction of astigmatism in all groups. Ninety-two percent of total eyes achieved a manifest refractive spherical equivalent within +/-0.5 of emmetropia. CONCLUSIONS: Corneal excimer laser refractive surgery seems to be equally effective to correct different residual errors, including astigmatism, in eyes implanted with intraocular lenses with various platforms for multifocality. PMID- 27617869 TI - Evaluation of Serum Superoxide Dismutase Activity, Malondialdehyde, and Zinc and Copper Levels in Patients With Keratoconus. AB - PURPOSE: The aim of this study was to evaluate the relationship between antioxidant superoxide dismutase (SOD) enzyme activity, malondialdehyde (MDA) as a lipid peroxidation marker, and some trace elements such as zinc (Zn) and copper (Cu) levels in patients with keratoconus. METHODS: A total of 58 patients with keratoconus and 53 control subjects with similar age and sex were evaluated in this study. The modified Krumeich keratoconus classification was used to divide the patients into 4 stages. Serum SOD activity, MDA, and zinc and copper levels were compared between the patient and control groups. RESULTS: The median serum SOD activity, MDA, and Zn and Cu levels were 27.2 (42.4-13.7) U/mL, 10.2 (11.9 8.5) nmol/mL, 87.9 (104.6-76.5) MUmol/L, and 103.2 (117.9-90.3) MUmol/L in the keratoconus group and 26.2 (32.5-14.4) U/mL, 8.8 (11.4-7.1) nmol/mL, 100.5 (121.1 81.8) MUmol/L, and 98.4 (120.3-83.4) MUmol/L in the control group, respectively. There was a statistically significant difference between the MDA and Zn levels of the keratoconus group and control subjects but not between the respective SOD activities or Cu levels (P = 0.016, P = 0.031, P = 0.440, and P = 0.376, respectively). We found no significant difference between the keratoconus group stages for serum SOD activity, serum MDA, and Zn and Cu levels (P > 0.05), and there was also no significant correlation between the keratoconus group stages and serum SOD activity, serum MDA, and Zn and Cu levels (P > 0.05). CONCLUSIONS: There is imbalance in the systemic oxidant/antioxidant status where Zn deficiency also plays a role in patients with keratoconus. PMID- 27617870 TI - Surgical Management of Limbal Dermoids Using Anterior Corneal Buttons From Descemet Stripping Automated Endothelial Keratoplasty Donor Tissue as Patch Grafts. AB - PURPOSE: To assess the surgical and clinical outcomes of anterior lamellar keratoplasty using anterior corneal buttons from Descemet stripping automated endothelial keratoplasty (DSAEK) donor tissue. METHODS: Retrospective data from 8 patients with unilateral limbal dermoids, treated between February 2011 and January 2016 at National Taiwan University Hospital, were analyzed. Donor corneas for DSAEK were divided into anterior and posterior lamellae using a 350-MUm microkeratome. Anterior corneal buttons were stored for up to 4 weeks in storage media before being used as patch grafts for anterior lamellar keratoplasty. RESULTS: Corneoscleral integrity was preserved in all cases. Three of the 8 patients showed improved best-corrected visual acuity after surgery. Three patients' astigmatism reduced by more than 0.75 diopters. All 8 patients had satisfactory cosmesis after surgery. Neovascularization at the graft-host junction and graft edema was noted in 1 patient and was treated using bevacizumab injection and topical steroid. CONCLUSIONS: Anterior corneal buttons obtained from DSAEK can be used as patch grafts for surgical management of limbal dermoids. This procedure achieved satisfactory cosmetic and visual outcomes in our study. This procedure may potentially allow one corneal tissue to be received by multiple patients. PMID- 27617871 TI - Reply. PMID- 27617872 TI - Sex Chromosome Analysis of Postmortem Corneal Endothelium After Sex-Mismatch Descemet Membrane Endothelial Keratoplasty. AB - PURPOSE: To identify the origin of corneal endothelial cells (host or donor) present on grafts at various time points after Descemet membrane endothelial keratoplasty (DMEK), using fluorescence in situ hybridization (FISH) of sex chromosomes on post mortem corneas with sex mismatch between the donor and host. METHODS: Corneoscleral buttons of 6 post mortem DMEK eyes of 4 patients, operated for Fuchs endothelial dystrophy, with an average postoperative time of 2.6 (+/ 1.8) years (range, 7 months-4.5 years), of 2.5 (+/-1.7) years (range, 7 months-4 years), were processed for FISH detection of XX (female) or XY (male)-labeling signals in corneal endothelial cells in the central area of the DMEK graft. Two male patients underwent bilateral DMEK with grafts from female donors, and 2 female patients underwent unilateral DMEK and received a graft from a male donor. RESULTS: FISH consistently showed the presence of donor endothelial cells across the graft area, with signaling of sex chromosomes opposite to the sex of the host. CONCLUSIONS: Donor endothelial cells may survive up to 4.5 years after DMEK. If so, the lower incidence of allograft rejection in DMEK may not be explained by early host cell replacement. Potential host cell migration may be limited by donor/recipient cell-cell contact inhibition. PMID- 27617873 TI - Reply. PMID- 27617874 TI - Visualization of Tear Clearance Using Anterior Segment Optical Coherence Tomography and Polymethylmethacrylate Particles. AB - We previously reported 2 new methods, anterior segment optical coherence tomography (AS-OCT) and polymethylmethacrylate particles suspended in fluorescein solution (PPF), for the evaluation of tear clearance and rapid tear flow after blinking (tear Krehbiel flow). Here, we investigated age-related OCT tear clearance and tear film thickness (TFT) and the potential correlation of OCT tear clearance and PPF velocity indicative of tear Krehbiel flow. Normal subjects separated into young and older groups received 5 MUL of saline solution into the lower conjunctival sac, and an image of the central lower eyelid tear meniscus was captured by AS-OCT immediately and 30 seconds after natural blinking. Tear meniscus height (TMH) and tear meniscus area (TMA) were measured, and their percentage decrease was defined as OCT clearance rate. A Spectralis OCT Anterior Segment Module captured the central corneal tear film layer for TFT measurements. OCT clearance rates were significantly higher in young versus older subjects (P = 0.0002). When all subjects were analyzed, age was significantly and negatively correlated with TMH clearance rate (r = -0.4928, P = 0.0003) and TMA clearance rate (r = -0.4596, P = 0.0008). TFT values were significantly and negatively correlated with age (r = -0.6662, P < 0.0001). A second experiment examined tear Krehbiel flow by measuring PPF velocity in frontal and medial gaze positions. The medial gaze position showed significantly increased PPF velocity compared with the frontal gaze position (P = 0.006). Significant and positive correlations were found between OCT clearance rates and PPF velocity (TMH rate: r = 0.2926, P = 0.0392; TMA rate: r = 0.3274, P = 0.0205). AS-OCT and PPF might be novel techniques for quantitative evaluation of tear clearance and Krehbiel flow. PMID- 27617875 TI - Applications of Biomaterials in Corneal Endothelial Tissue Engineering. AB - When corneal endothelial cells (CECs) are diseased or injured, corneal endothelium can be surgically removed and tissue from a deceased donor can replace the original endothelium. Recent major innovations in corneal endothelial transplantation include replacement of diseased corneal endothelium with a thin lamellar posterior donor comprising a tissue-engineered endothelium carried or cultured on a thin substratum with an organized monolayer of cells. Repairing CECs is challenging because they have restricted proliferative ability in vivo. CECs can be cultivated in vitro and seeded successfully onto natural tissue materials or synthetic polymeric materials as grafts for transplantation. The optimal biomaterials for substrata of CEC growth are being investigated. Establishing a CEC culture system by tissue engineering might require multiple biomaterials to create a new scaffold that overcomes the disadvantages of single biomaterials. Chitosan and polycaprolactone are biodegradable biomaterials approved by the Food and Drug Administration that have superior biological, degradable, and mechanical properties for culturing substratum. We successfully hybridized chitosan and polycaprolactone into blended membranes, and demonstrated that CECs proliferated, developed normal morphology, and maintained their physiological phenotypes. The interaction between cells and biomaterials is important in tissue engineering of CECs. We are still optimizing culture methods for the maintenance and differentiation of CECs on biomaterials. PMID- 27617876 TI - "Toward a Bright Future for Corneal Research and Practice in Japan and Abroad," 21st Annual Meeting of the Kyoto Cornea Club, November 27 and 28, 2015. PMID- 27617878 TI - Synthesis and anthelmintic activity of coumarin-imidazole hybrid derivatives against Dactylogyrus intermedius in goldfish. AB - With an intention to find more potent anti-parasite agents, four bromoalkane substituted coumarin derivatives (1-4) and twenty coumarin-imidazole hybrid derivatives were synthesized and screened for their anthelmintic activity and the acute toxicity. Anti-parasites results confirmed that most coumarin derivatives retained their anthelmintic activity against Dactylogyrus intermedius at the dose range from 1 to 10mg/L. Among the candidates, compound 23 showed the best anthelmintic activity than other compounds against D. intermedius infestation with EC50 value of 0.85mg/L. The structure-activity relationship analysis confirmed that the anthelmintic activities of derivatives were determined by the length of 'linker' (R1substitute position) and the substitute group in R2 position. The active data confirmed that six carbon atoms length of 'linker' and benzimidazole substitute group can increased the anthelmintic activity of compound, significantly. On the basis of these results, compound 23 can be used as a potential lead compound for the development of commercial drug against D. intermedius. PMID- 27617879 TI - Common Sense: Use All Proven Pain Methods in a Comprehensive Strategy to Prevent Opioid Abuse. PMID- 27617877 TI - Bilateral Alterations in Corneal Nerves, Dendritic Cells, and Tear Cytokine Levels in Ocular Surface Disease. AB - This review summarizes the recent literature regarding corneal imaging in human subjects using in vivo confocal microscopy. It also covers the recent literature on corneal immune cells, nerves, and tear cytokine levels in ocular surface diseases as well as corneal immune privilege. The significance of interactions between corneal immune cells and nerves in health, neurotrophic keratopathy, and infectious keratitis is discussed. Furthermore, bilateral alterations of immune cells and nerves in clinically unilateral corneal diseases and the link to changes of tear cytokines or neuropeptide levels in contralateral eyes are described. Recent studies reported increased density and morphologic changes of corneal dendritic cells in ocular surface disease that correlated with a decrease in subbasal nerve and corneal nerve density, suggesting potential interactions between the immune and nervous systems in the cornea. Although the relevance of tear cytokines is poorly understood, tear cytokines might have an important role in the pathogenesis of ocular surface diseases. In humans and experimental animal models, alterations in immune cells, cytokines, and immunomodulatory neuropeptide levels in contralateral eyes might mediate the incidence of bilateral infectious keratitis and loss of immune privilege of the cornea in bilateral corneal transplantation or neurotrophic keratopathy cases. The discovery of bilateral alterations of immune cells and nerves in ocular surface diseases is considered the missing link between the immune and nervous systems in the cornea, and demonstrates how studies of animal models and humans aid our understanding of human corneal disease phenomena. PMID- 27617880 TI - Multiscale Characterization of Engineered Cardiac Tissue Architecture. AB - In a properly contracting cardiac muscle, many different subcellular structures are organized into an intricate architecture. While it has been observed that this organization is altered in pathological conditions, the relationship between length-scales and architecture has not been properly explored. In this work, we utilize a variety of architecture metrics to quantify organization and consistency of single structures over multiple scales, from subcellular to tissue scale as well as correlation of organization of multiple structures. Specifically, as the best way to characterize cardiac tissues, we chose the orientational and co-orientational order parameters (COOPs). Similarly, neonatal rat ventricular myocytes were selected for their consistent architectural behavior. The engineered cells and tissues were stained for four architectural structures: actin, tubulin, sarcomeric z-lines, and nuclei. We applied the orientational metrics to cardiac cells of various shapes, isotropic cardiac tissues, and anisotropic globally aligned tissues. With these novel tools, we discovered: (1) the relationship between cellular shape and consistency of self assembly; (2) the length-scales at which unguided tissues self-organize; and (3) the correlation or lack thereof between organization of actin fibrils, sarcomeric z-lines, tubulin fibrils, and nuclei. All of these together elucidate some of the current mysteries in the relationship between force production and architecture, while raising more questions about the effect of guidance cues on self-assembly function. These types of metrics are the future of quantitative tissue engineering in cardiovascular biomechanics. PMID- 27617881 TI - FSees: Customized Enumeration of Chemical Subspaces with Limited Main Memory Consumption. AB - In the search for new marketable drugs, new ideas are required constantly. Particularly with regard to challenging targets and previously patented chemical space, designing novel molecules is crucial. This demands efficient and innovative computational tools to generate libraries of promising molecules. Here we present an efficient method to generate such libraries by systematically enumerating all molecules in a specific chemical space. This space is defined by a fragment space and a set of user-defined physicochemical properties (e.g., molecular weight, tPSA, number of H-bond donors and acceptors, or predicted logP). In order to enumerate a very large number of molecules, our algorithm uses file-based data structures instead of memory-based ones, thus overcoming the limitations of computer main memory. The resulting chemical library can be used as a starting point for computational lead-finding technologies, like similarity searching, pharmacophore mapping, docking, or virtual screening. We applied the algorithm in different scenarios, thus creating numerous target-specific libraries. Furthermore, we generated a fragment space from all approved drugs in DrugBank and enumerated it with lead-like constraints, thus generating 0.5 billion molecules in the molecular weight range 250-350. PMID- 27617883 TI - Neurocognitive functioning in children with developmental dyslexia and attention deficit/hyperactivity disorder: Multiple deficits and diagnostic accuracy. AB - INTRODUCTION: This study aimed to investigate the neurocognitive functioning of children with developmental dyslexia (DD) and attention-deficit/hyperactivity disorder (ADHD). METHOD: Four groups of children between the ages of 8 and 10 years participated in the study: typically developing children (TDC; N = 34), children with DD-only (N = 32), children with ADHD-only (N = 32), and children with DD+ADHD (N = 18). RESULTS: Children with DD and ADHD exhibited significant weaknesses on almost all neurocognitive measures compared with TDC. Large effect sizes were observed for naming speed and phonological awareness. The comorbid group showed deficits consistent with both DD and ADHD without additional impairments. Results from binary logistic regression and receiver-operating characteristic (ROC) curve analyses suggested that some neurocognitive measures revealed an adequate sensitivity for the clinical diagnosis of both neurodevelopmental disorders. Specifically, naming speed and phonological awareness were the strongest predictors to correctly discriminate both disorders. CONCLUSIONS: Taken together, the results lend support to the multiple cognitive deficit hypothesis showing a considerable overlap of neurocognitive deficits between both disorders. PMID- 27617884 TI - The Relationship Between Speech Production and Speech Perception Deficits in Parkinson's Disease. AB - Purpose: This study investigated the possible relationship between hypokinetic speech production and speech intensity perception in patients with Parkinson's disease (PD). Method: Participants included 14 patients with idiopathic PD and 14 matched healthy controls (HCs) with normal hearing and cognition. First, speech production was objectified through a standardized speech intelligibility assessment, acoustic analysis, and speech intensity measurements. Second, an overall estimation task and an intensity estimation task were addressed to evaluate overall speech perception and speech intensity perception, respectively. Finally, correlation analysis was performed between the speech characteristics of the overall estimation task and the corresponding acoustic analysis. The interaction between speech production and speech intensity perception was investigated by an intensity imitation task. Results: Acoustic analysis and speech intensity measurements demonstrated significant differences in speech production between patients with PD and the HCs. A different pattern in the auditory perception of speech and speech intensity was found in the PD group. Conclusions: Auditory perceptual deficits may influence speech production in patients with PD. The present results suggest a disturbed auditory perception related to an automatic monitoring deficit in PD. PMID- 27617885 TI - Corrigendum to "Cortical thickness and VBM in young women at risk for familial depression and their depressed mothers with positive family history" [Psychiatry Res.: Neuroimaging 252 (2016) 1-9]. PMID- 27617886 TI - Probing the Photosensitizing and Inhibitory Effects of Dissolved Organic Matter by Using N,N-dimethyl-4-cyanoaniline (DMABN). AB - Dissolved organic matter (DOM) can act as a photosensitizer and an inhibitor in the phototransformation of several nitrogen-containing organic contaminants in surface waters. The present study was performed to select a probe molecule that is suitable to measure these antagonistic properties of DOM. Out of nine studied nitrogen-containing aromatic compounds, 4-cyanoaniline, N,N-dimethyl-4 cyanoaniline (DMABN), sotalol (a beta-blocker) and sulfadiazine (a sulfonamide antibiotic) exhibited a marked photosensitized transformation that could be substantially inhibited by addition of phenol as a model antioxidant. The photosensitized transformation of DMABN, the selected probe compound, was characterized in detail under UV-A and visible irradiation (lambda > 320 nm) to avoid direct phototransformation. Low reactivity of DMABN with singlet oxygen was found (second-order rate constant <2 * 107 M-1 s-1). Typically at least 85% of the reactivity of DMABN could be inhibited by DOM or the model antioxidant phenol. The photosensitized transformation of DMABN mainly proceeded (>72%) through demethylation yielding N-methyl-4-cyanoaniline and formaldehyde as primary products. In solutions of standard DOM extracts and their mixtures the phototransformation rate constant of DMABN was shown to vary nonlinearly with the DOM concentration. Model equations describing the dependence of such rate constants on DOM and model antioxidant concentrations were successfully used to fit experimental data. PMID- 27617882 TI - Formation and Biological Targets of Quinones: Cytotoxic versus Cytoprotective Effects. AB - Quinones represent a class of toxicological intermediates, which can create a variety of hazardous effects in vivo including, acute cytotoxicity, immunotoxicity, and carcinogenesis. In contrast, quinones can induce cytoprotection through the induction of detoxification enzymes, anti-inflammatory activities, and modification of redox status. The mechanisms by which quinones cause these effects can be quite complex. The various biological targets of quinones depend on their rate and site of formation and their reactivity. Quinones are formed through a variety of mechanisms from simple oxidation of catechols/hydroquinones catalyzed by a variety of oxidative enzymes and metal ions to more complex mechanisms involving initial P450-catalyzed hydroxylation reactions followed by two-electron oxidation. Quinones are Michael acceptors, and modification of cellular processes could occur through alkylation of crucial cellular proteins and/or DNA. Alternatively, quinones are highly redox active molecules which can redox cycle with their semiquinone radical anions leading to the formation of reactive oxygen species (ROS) including superoxide, hydrogen peroxide, and ultimately the hydroxyl radical. Production of ROS can alter redox balance within cells through the formation of oxidized cellular macromolecules including lipids, proteins, and DNA. This perspective explores the varied biological targets of quinones including GSH, NADPH, protein sulfhydryls [heat shock proteins, P450s, cyclooxygenase-2 (COX-2), glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase 1, (NQO1), kelch-like ECH-associated protein 1 (Keap1), IkappaB kinase (IKK), and arylhydrocarbon receptor (AhR)], and DNA. The evidence strongly suggests that the numerous mechanisms of quinone modulations (i.e., alkylation versus oxidative stress) can be correlated with the known pathology/cytoprotection of the parent compound(s) that is best described by an inverse U-shaped dose-response curve. PMID- 27617888 TI - Rotational gait patterns in children and adolescents following tension band plating of idiopathic genua valga. AB - Literature suggests that children and adolescents with idiopathic genua valga present with considerable gait deviations in frontal and transverse planes, including altered frontal knee moments, reduced external knee rotation, and increased external hip rotation. This study aimed to evaluate gait parameters in these patients after surgical correction using tension band plating (TBP). We prospectively evaluated 24 consecutive, skeletally immature patients, who received full-length standing radiographs and three-dimensional gait analysis before and after correction, and compared the results observed to a group of 11 typically developing peers. Prior to TBP the cohort showed significantly decreased (worse) internal frontal knee moments compared to the control group. After axis correction the mean and maximum knee moments changed significantly into normalized knee moments (p < 0.0001). In the transverse plane, only the foot progression angle (p = 0.020) changed significantly following intervention. Post correction knee moments were similar to controls (p = 0.175), but the patient cohort exhibited a significantly decreased knee external rotation (p = 0.004) and increased external hip rotation (p < 0.001) during gait. In addition, the effect of transverse plane changes on knee moments in patients with restored, straight limb axis was calculated. Hence, patients with restored alignment but persistence of decreased external knee rotation demonstrated significantly greater knee moments than those without rotational abnormalities (p = 0.001). This study found that frontal knee moments during gait normalized in children with idiopathic genua valga after surgery. However, decreased external knee rotation and increased external hip rotation during gait persisted in the study cohort. Despite radiological correction, decreased external rotation during gait was associated with increases in medial knee loading. Surgical correction for children with genua valga but normal knee moments may be detrimental, due to redistribution of dynamic knee loading into the opposite joint compartment. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1617-1624, 2017. PMID- 27617887 TI - Emotional Implications of Weight Stigma Across Middle School: The Role of Weight Based Peer Discrimination. AB - This study considered the emotional consequences of weight stigmatization in early adolescence by examining the effects of weight-based peer discrimination across middle school. Sampled across 26 urban middle schools, 5,128 youth (52% girls) with complete body mass index data at sixth or 7th grade were included: 30% Latino, 21% White, 14% East/Southeast Asian, 14% Multiethnic, 12% African American/Black, and 9% from other specific ethnic groups. About one third of the sample reported at least one weight-discrimination incident at 7th grade. Controlling for sixth-grade adjustment, perceptions of weight-based peer discrimination at 7th grade were stronger predictors of body dissatisfaction, social anxiety, and loneliness (and somatic symptoms for girls but not boys) at 8th-grade than 7th-grade body mass index. Moreover, heavier body stature during the 1st year in middle school was associated with increased body dissatisfaction by the end of middle school in part due to weight-related disrespectful, exclusionary, and demeaning treatment by peers. Weight-based peer discrimination helps us understand one of the stigmatizing mechanisms underlying the relation between heavy body stature and the progression of emotional problems in early adolescence. PMID- 27617889 TI - Epidemiology of Amyotrophic Lateral Sclerosis: A Population-Based Study in Israel. AB - BACKGROUND: Globally, the annual incidence and prevalence of amyotrophic lateral sclerosis (ALS) are estimated at 1.9 and 4.5 per 100,000 population, respectively. This study is aimed at describing the epidemiology of ALS in Israel in a real-world setting. METHODS: A retrospective study was performed using the databases of Maccabi Healthcare Services (MHS), a 2-million-member health maintenance organization in Israel. The study included all MHS adults diagnosed with ALS between 1997 and 2013. In 2013, characteristics of ALS patients were compared to those of age-sex-matched patients without ALS. Survival after ALS diagnosis was assessed until death and until tracheostomy or death (follow-up through 2014). RESULTS: In 2013 (n = 158), the prevalence of ALS was 8.1 per 100,000 population in MHS. In 1997-2013, a total of 375 ALS patients were diagnosed, corresponding to an average annual incidence of 1.8 per 100,000 population in MHS. The median survival from diagnosis to death was 3.5 years (95% CI 2.9-4.1), with approximately 28% surviving at least 10 years. Median tracheostomy-free survival was 2.5 years (95% CI 2.1-2.9). CONCLUSIONS: Results suggest that there is a relatively high prevalence of ALS in Israel. Further research is needed to investigate factors that may contribute to the survival of patients with ALS in Israel. PMID- 27617890 TI - [Lung neuroendocrine large-cell carcinoma in young women - An unusual presentation]. AB - INTRODUCTION: Lung neuroendocrine large-cell carcinoma (LNELCC) is a rare tumour with a poor prognosis. There are very few guidelines for LNELCC treatment but a better knowledge of its biology could improve the treatment and prognosis of this malignancy. OBSERVATIONS: We present the cases of 2 patients who presented initially with early stage carcinoid tumours treated with surgery. Both patients had further new neuroendocrine disease diagnosed because of intermittent carcinoid syndrome, predominantly occurring at the same time as menstruation. They were then diagnosed with metastatic LNELCC. They were treated with first line cisplatin-etoposide and second-line octreotide based on the protocol used for treatment of gastro-intestinal neuroendocrine tumours. They both had a good prognosis with no disease progression to date. CONCLUSIONS: The clinical characteristics of these cases raise several questions about the pathophysiology of LNELCC and may suggest potential new treatment options. The unusual clinical presentation and good prognosis may be explained either by the second-line treatment choice or by potential molecular or hormonal biomarkers. There is a need to investigate these potential biomarkers further since they could be new therapeutic targets. PMID- 27617891 TI - Imaging and Intracellular Tracking of Cancer-Derived Exosomes Using Single Molecule Localization-Based Super-Resolution Microscope. AB - Exosomes are small membrane vesicles secreted by cells and enriched with plenty of proteins. Considering their significant roles in different physical activities and potential value for diagnostic drug delivery, researchers have put great efforts in in vitro tracking and content analysis of exosomes. Recently, the emergence of different kinds of super-resolution microscopy provides powerful tools for exosome study. Here, we demonstrate the application of single-molecule localization based super-resolution imaging technique in the imaging and tracking of cancer-derived exosomes. In the experiment, first, cancer-derived exosomes are extracted from the culture media of tumor cells. Then the exosome membrane receptors are labeled with photoswitchable probes, which allow super-resolution imaging of these membrane receptors via photoactivated localization microscopy (PALM) or stochastic optical reconstruction microscopy (STORM). By using human breast cancer cell-derived exosomes, we demonstrated simultaneous dual-color PALM/STORM imaging of two kinds of membrane receptors on the exosome membrane. Moreover, the successful labeling and imaging of exosomes make it possible to observe the interaction between cancer-derived exosomes and normal cells. Meanwhile, we realized the colocalization of cancer-derived exosomes and lysosomes in recipient cells with PALM/STORM imaging. Since exosomes play a vital role in intercellular communications, we anticipate that the presented PALM/STORM based imaging and tracking of exosomes holds a great potential in the investigation of the mechanism of exosome-mediated cancer metastasis. PMID- 27617892 TI - Cytokine Effects on Mechano-Induced Electrical Activity in Atrial Myocardium. AB - : The role of cytokines as regulators of stretch-related mechanisms is of special importance since mechano-sensitivity plays an important role in a wide variety of biological processes. Here, we elucidate the influence of cytokine application on mechano-sensitivity and mechano-transduction. The atrial myocardial stretch induces production of interleukin (IL)-2, IL-6, IL-13, IL-17A, and IL-18 with exception of tumor necrosis factor alpha (TNF-alpha), IL-1beta, and vascular endothelial growth factor B (VEGF-B). Positive ionotropic effect was specific for VEGF-B, negative ionotropic effects were specific for TNF-alpha, IL-1beta, IL-2, IL-6, IL-13, IL-17A and IL-18, while IL-1alpha doesn't show direct ionotropic effect. The IL-2, IL-6, IL-17A, IL-18, and VEGF-B cause elongation of the APD, in comparison with the reduced APD caused by the IL-13. The TNF-alpha, IL-1beta, and IL-18 influences L-type Ca2+ channels, IL-2 has an inhibitory effect on the fast Na+ channels while IL-17A and VEGF-B were specific for Kir channels. With exception of the IL-1alpha, IL-2, and VEGF-B, all analyzed cytokines include nitric oxide dependent signaling with resultant combined effects on mechano-gated and Ca2+ channels. The relationships between these pathways and the time dependence of their activation are of important considerations in the evaluation of cytokine-induced electrical abnormality, specific for cardiac dysfunctions. In general, the discussion presented in this review covers research devoted to counterbalance between different cytokines in the regulation of stretch-induced effects in rat atrial myocardium. ABBREVIATIONS: APs: action potentials; APD25: action potential durations to 25% of re-polarization; APD50: action potential durations to 50% of repolarization; APD90: action potential durations to 90% of repolarization; MGCs: mechanically gated channels. PMID- 27617893 TI - Reactions of Ruthenium Complexes Containing Pentatetraenylidene Ligand. AB - Two ruthenium acetylide complexes [Ru]-C=C-C=C-C(OR)(C3 H5 )2 (2, R=H and 2 a, R=CH3 ; [Ru]=Cp(PPh3 )2 Ru) each with two cyclopropyl rings were synthesized from TMS-C=C-C=C-C(OH)(C3 H5 )2 (1; TMS=trimethylsilyl). Treatments of 2 and 2 a with allyl halide in the presence of KPF6 afforded the vinylidene complexes 3 and 3 a, respectively. When NH4 PF6 was used, instead of KPF6 , additional ring-opening reaction took place on one of the three-membered ring. Treatment of [Ru]Cl with 1,3-butadiyne (6), bearing an epoxide ring, afforded acetylide complex 7 with a furyl ring. Treatment of 2 a with Ph3 CPF6 presumably afforded pentatetraenylidene complex {[Ru]=C=C=C=C=C(C3 H5 )2 }[PF6 ] (10), which was not isolated. Additions of various alcohols in a solution of 10 generated a number of disubstituted allenylidene complexes {[Ru]=C=C=C(OR)-C=C(C3 H5 )2 }[PF6 ] (11). Treatment of 11 with K2 CO3 afforded the acetylide complex 12 bearing a carbonyl group, characterized by single X-ray diffraction analysis. Addition of a primary amine to 10 caused cleavage of the farthermost C=C bond and several allenylidene complexes {[Ru]=C=C=C(Me)(NHR)}[PF6 ] (18) were isolated. PMID- 27617894 TI - Zika Virus Is More Like Rubella Than Human Immunodeficiency Virus-Reply. PMID- 27617900 TI - The Academy of Breastfeeding Medicine Is an International Authority: Who Are Our Partners and Allies? PMID- 27617901 TI - Two- and Three-Centered Hydrogen Bonds Involving Organic Fluorine Stabilize Conformations of Hydrazide Halo Derivatives: NMR, IR, QTAIM, NCI, and Theoretical Evidence. AB - The presence of two- and three-centered hydrogen bonds (HB) of the type H(N)...X C and C?O...H(N)...X-C, respectively, involving organic fluorine in the synthesized hydrazide halo derivatives have been convincingly established by extensive multidimensional NMR studies. The stabilized conformation of the molecules involving two- and three-centered HBs derived by NMR studies have been further confirmed by density functional theory (DFT)-based calculations, such as quantum theory of atoms in molecules (QTAIM), noncovalent interaction (NCI), and relaxed potential energy scan. PMID- 27617902 TI - Big Versus Small Data and the Generalizability of the Rate of Computed Tomography Overuse in Minor Head Injury. PMID- 27617903 TI - Bioactive Lupane and Hopane Triterpenes from Lepisanthes senegalensis. AB - Two lupane and hopane caffeates (1 and 4) and two hopane coumarates (2 and 3) along with eight known compounds (5-12) were isolated from stems and roots of Lepisanthes senegalensis. Their structures were established on the basis of spectroscopic techniques. The structure of compound 2 was confirmed by single crystal X-ray diffraction analysis. Triterpenes 1 and 4-6 showed cytotoxicity against the NCI-H187 cell line with IC50 values of 31.5, 28.5, 16.2, and 4.0 uM, respectively. However, these compounds also showed cytotoxicity against Vero cells, with IC50 values of 75.5, 16.6, 8.9, and 5.0 uM, respectively. In addition, compound 6 exhibited a moderate antimalarial activity with an IC50 value of 4.5 uM. PMID- 27617904 TI - Fam60A plays a role for production stabilities of recombinant CHO cell lines. AB - Recombinant CHO (Chinese hamster ovary) cell lines producing therapeutic proteins often lose their production capability during long-term cultivation. To ensure that CHO production cell lines can be up-scaled to high-volume bioreactors, labor intensive stability studies of several months have to be performed to deselect clones that are losing productivity over time. The ability to predict whether clones will produce recombinant proteins at constant high levels, for example, through determination of biomarkers such as expression of specific genes, plasmid integration sites, or epigenetic patterns, or even to improve CHO host cell lines to increase the probability of the generation of stable clones would be highly beneficial. Previously, we reported that the lack of a telomeric region of chromosome 8 correlates with increased productivities and higher production stabilities of monoclonal antibody expressing CHO cell lines (Ritter A, Voedisch B, Wienberg J, Wilms B, Geisse S, Jostock T, Laux H. 2016a. Biotechnol Bioeng 113(5):1084-1093). Herein, we describe that the knock-out of the gene Fam60A, which is one of the genes located within the telomeric region of chromosome 8, in CHO-K1a cells leads to the isolation of significantly more clones with higher protein production stabilities of monoclonal antibodies during long-term cultivation. Biotechnol. Bioeng. 2017;114: 701-704. (c) 2016 Wiley Periodicals, Inc. PMID- 27617905 TI - Evolutionary game theory using agent-based methods. AB - Evolutionary game theory is a successful mathematical framework geared towards understanding the selective pressures that affect the evolution of the strategies of agents engaged in interactions with potential conflicts. While a mathematical treatment of the costs and benefits of decisions can predict the optimal strategy in simple settings, more realistic settings such as finite populations, non vanishing mutations rates, stochastic decisions, communication between agents, and spatial interactions, require agent-based methods where each agent is modeled as an individual, carries its own genes that determine its decisions, and where the evolutionary outcome can only be ascertained by evolving the population of agents forward in time. While highlighting standard mathematical results, we compare those to agent-based methods that can go beyond the limitations of equations and simulate the complexity of heterogeneous populations and an ever changing set of interactors. We conclude that agent-based methods can predict evolutionary outcomes where purely mathematical treatments cannot tread (for example in the weak selection-strong mutation limit), but that mathematics is crucial to validate the computational simulations. PMID- 27617907 TI - Isolated Mesoporous Microstructures Prepared by Stress Localization-Induced Crack Manipulation. AB - Cracks observed in brittle materials are mostly regarded as defects or failures. However, they can be a valuable tool when implemented in a controlled way. Here, we introduce a strategy to control the crack propagation of mesoporous micropatterns (prisms and pyramids), which leads to the isolation of well-defined microstructures. Mesoporous micropatterns were fabricated by the soft imprinting technique with wet TiO2 nanoparticle (NP) pastes, followed by sintering to remove organic components. Since the volume of the paste significantly shrinks during the sintering step, stress is localized at the edge of micropatterns, in good agreement with finite element method simulations, creating well-defined cracks and their propagation. It was demonstrated that the degree of stress localization is determined by the thickness of residual layers, NP size, and heating rate. After controlled crack propagation and delamination of microparticles from the substrates, mesoporous microwires and microparticles were successfully produced and functionalized from the isolated mesoporous prisms and pyramids. The method proposed in this study for controlled crack manipulation and delamination opens a door for straightforward and economical fabrication of well-defined mesoporous microparticles. PMID- 27617909 TI - Initial Experience: Alleviation of Pain with Percutaneous CT-Guided Cryoablation for Recurrent Retroperitoneal Soft-Tissue Sarcoma. AB - PURPOSE: To evaluate the pain-alleviating effect of computed tomography (CT) guided percutaneous cryoablation for recurrent retroperitoneal soft-tissue sarcomas (RPSs). MATERIALS AND METHODS: Data from 19 men and 20 women (median age, 50.3 y) with recurrent malignant RPS who underwent percutaneous cryoablation were reviewed retrospectively. A total of 50 tumors were treated by cryoablation, including a single tumor in 29 patients, 2 tumors in 9, and 3 tumors in 1. Adverse events and analgesic outcomes were compared as a function of tumor size (< 10 cm and >= 10 cm). Efficacy was assessed based on modified Response Evaluation Criteria In Solid Tumors and progression-free survival (PFS). RESULTS: Grade 1/2 adverse events included fever (n = 17), emesis (n = 7), frostbite (n = 5), and local pain (n = 4). The median follow-up period and PFS were 18.5 months (range, 12-42 mo) and 13.4 months +/- 6.2, respectively. At the end of follow-up, 13 patients had died and 26 were living. The mean severe local pain scores on pretreatment day 1 and posttreatment days 1, 5, 10, 15, 20, and 25 were 7.49, 7.40, 6.51, 5.81, 5.35, 5.04, and 5.44, respectively, and significant differences versus pretreatment (P < .001) were reported for posttreatment days 5-25. Immediate relief occurred more frequently in the small-tumor group (4 of 7; 57.1%; P = .018), whereas delayed relief occurred more frequently in the large tumor group (17 of 22; 77.3%; P = .030). CONCLUSIONS: Minimally invasive percutaneous cryoablation improves local pain and is a feasible treatment for recurrent RPSs. PMID- 27617912 TI - Development of N-Substituted Hydroxamic Acids with Pyrazolone Leaving Groups as Nitrosocarbonyl Precursors. AB - A novel class of nitrosocarbonyl precursors, N-substituted hydroxamic acids with pyrazolone leaving groups (NHPY), has been synthesized. Under physiological conditions, these compounds generate nitrosocarbonyl intermediates, which upon hydrolysis release nitroxyl (azanone, HNO) in excellent yields. The amount and rate of nitrosocarbonyl generation are dependent on the nature of the pyrazolone leaving groups and significantly on the structural properties of the NHPY donors. Pyrazolones have been found to be efficient nitrosocarbonyl traps, undergoing an N-selective nitrosocarbonyl aldol reaction. This trapping reaction has been used to confirm the involvement of nitrosocarbonyl intermediates in NHPY aqueous decomposition. In addition, NHPY compounds are shown to generate nitrosocarbonyls efficiently under mild basic conditions in organic solvent and may therefore also enjoy synthetic utility. PMID- 27617908 TI - The emerging landscape of circular RNA in life processes. AB - Circular RNAs (circRNAs) are a novel class of non-coding RNA that assumes a covalently closed continuous conformation. CircRNAs were previously thought to be the byproducts of splicing errors caused by low abundance and the technological limitations. With the recent development of high-throughput sequencing technology, numerous circRNAs have been discovered in many species. Recent studies have revealed that circRNAs are stable and widely expressed, and often exhibit cell type-specific or tissue-specific expression. Most circRNAs can be generated from exons, introns, or both. Remarkably, emerging evidence indicates that some circRNAs can serve as microRNA (miRNA) sponges, regulate transcription or splicing, and can interact with RNA binding proteins (RBPs). Moreover, circRNAs have been reported to play essential roles in myriad life processes, such as aging, insulin secretion, tissue development, atherosclerotic vascular disease risk, cardiac hypertrophy and cancer. Although circRNAs are ancient molecules, they represent a newly appreciated form of noncoding RNA and as such have great potential implications in clinical and research fields. Here, we review the current understanding of circRNA classification, function and significance in physiological and pathological processes. We believe that future research will increase our understanding of the regulation and function of these novel molecules. PMID- 27617913 TI - Gender Differences and Correlated Factors of Heroin Use Among Heroin Users. AB - BACKGROUND: Gender differences in illicit drug use are becoming increasingly recognized. However, there are few studies concerning differences between male and female heroin users in China. OBJECTIVES: The study aimed to explore gender differences in terms of socio-demographic characteristics, drug-related behaviors, and treatment history among a heroin-using population in China. METHODS: A cross-sectional study was conducted in four cities in December 2013. A total of 788 participants were recruited from several types of sites in each city: compulsory detoxification centers, methadone maintenance treatment clinics, and detention facilities. The data were collected via a self-administered questionnaire. Analysis of variance, chi-square test, and multivariate logistic regression analyses were conducted to examine gender differences in socio demographic characteristics, drug-related behaviors, and treatment history. RESULTS: Female heroin users were more likely to be unemployed, have more education, and use heroin with their spouse/companion (p <.05). Male heroin users were more likely to be in detention facilities and MMT clinics, and relapse when they felt hopeless (p <.05). Conclusions/Importance: Although there were some similarities between male and female heroin users, significant gender differences do exist in some aspects of socio-demographic characteristics and heroin use. The data provide evidence that interventions aimed at preventing the initiation of heroin use and reducing relapse should take gender into account. PMID- 27617914 TI - Loving transgressions: Queer of color bodies, affective ties, transformative community. AB - This introductory article considers the importance of queer woman of color theorizations of affect in thinking more fully the recent interdisciplinary turn to affect. The affective turn has vitally invited culture and feminist critics to interrogate emotion beyond the individual to examine the political and cultural production of emotion. Even as women of color are often associated with excessive affect, the theoretical contributions women of color make to the field of affect studies are often overlooked. Our introduction and this special issue more broadly examine how this solipsism shapes projects invested in critical knowledge production, as well as the stakes of centering a queer woman of color genealogy. For instance, we argue for the importance of retaining U.S. third-world feminist concepts-like interpellation, oppositional consciousness, and the generative force of negative affects-even as they fall out of favor within affect studies. Centering theory that emerges from the vexed spaces of queer women of color lived experiences generates a vital interdisciplinary conversation that contributes to the ongoing political task of mobilizing affect for social action as a critical praxis. In the articles that follow we see this critical praxis at work in the form of community organizing, music, poetry, and performance art. PMID- 27617916 TI - Governance of malaria prevention: How decision-makers' and pregnant women's sensemaking contribute to unintended consequences. AB - Although malaria in pregnancy predisposes women to increased perinatal mortality and morbidity, complex issues underlie its persistence. To develop a better understanding of the factors affecting women's access to Intermittent Preventive Treatment in Benin, we used the theoretical lens of "sensemaking" to clarify policymakers', health professionals', and women's perspectives concerning preventive policies and barriers to access. Several assumptions were found to underlie Benin's malaria preventive policy that contribute to the unintended effect of deterring pregnant women in poverty from accessing preventive treatment. Health system dysfunctions including drug shortages and deficiencies in health care professionalism exacerbate the unintended effect. PMID- 27617918 TI - Classical/Non-classical Polyoxometalate Hybrids. AB - Two polyanions [SeI V2 PdII4 WVI14 O56 H]11- and [SeI V4 PdII4 WVI28 O108 H12 ]12 are the first hybrid polyoxometalates in which classical (Group 5/6 metal based) and non-classical (late transition-metal based) polyoxometalate units are joined. Requiring no supporting groups, this co-condensation of polyoxotungstate and isopolyoxopalladate constituents also provides a logical link between POM-PdII coordination complexes and the young subclass of polyoxopalladates. Solid-state, solution, and gas-phase studies suggest interesting specific reactivities for these hybrids and point to several potential derivatives and functionalization strategies. PMID- 27617920 TI - Going Viral. PMID- 27617919 TI - Perceptions About the Present and Future of Surgical Simulation: A National Study of Mixed Qualitative and Quantitative Methodology. AB - OBJECTIVES: Assess expert opinion on the current and future role of simulation in surgical education. DESIGN: Expert opinion was sought through an externally validated questionnaire that was disseminated electronically. PARTICIPANTS: Heads of Schools of Surgery (HoS) (and deputies) and Training Program Directors (TPD) (and deputies). RESULTS: Simulation was considered a good training tool (HoS: 15/15, TPD: 21/21). The concept that simulation is useful mostly to novices and for basic skills acquisition was rejected (HoS: 15/15, TPDs: 21/21; HoS: 13/15, TPDs: 18/21). Further, simulation is considered suitable for teaching nontechnical skills (HoS: 13/15, TPDs: 20/21) and re-enacting stressful situations (HoS: 14/15, TPDs: 15/21). Most respondents also felt that education centers should be formally accredited (HoS: 12/15, TPDs: 16/21) and that consultant mentors should be appointed by every trust (HoS: 12/15, TPDs: 19/21). In contrast, there were mixed views on its use for trainee assessment (HoS: 6/15, TPDs: 14/21) and whether it should be compulsory (HoS: 8/15, TPDs: 11/21). CONCLUSION: The use of simulation for the acquirement of both technical and nontechnical skills is strongly supported while views on other applications (e.g., assessment) are conflicting. Further, the need for center accreditation and supervised, consultant-led teaching is highlighted. PMID- 27617922 TI - Screening of FDA-Approved Drugs for Treatment of Emerging Pathogens. AB - The current outbreaks of Middle East Respiratory Syndrome (MERS) and Ebolavirus (EboV) have revealed a gap in the development and availability of drugs to treat these infections. To date, there are no approved treatments for patients infected with MERS coronavirus (MERS-CoV), a virus that continues to infect new patients and that has now spread from the Middle East to Asia. Despite a downward trend in the number of new EboV cases in West Africa, new infections are still occurring, and many patients continue to suffer from this illness. People infected with MERS and Ebola viruses receive only supportive care in hopes of recovery. Investigation into repurposing drugs approved by the FDA is gaining interest. To identify better treatment strategies, several groups have used drug screens to repurpose FDA-approved drugs as inhibitors of MERS-CoV and EboV. PMID- 27617923 TI - Forces and Structures of the Herpes Simplex Virus (HSV) Entry Mechanism. AB - This paper discusses physical and structural aspects of the mechanisms herpes simplex virus (HSV) uses for membrane fusion. Calculations show that herpes simplex virus glycoprotein D has such avidity for its receptors that it can hold the virion against the plasma membrane of a neuron strongly enough for glycoprotein B (gB) to disrupt both leaflets of the bilayer. The strong electric field generated by the cell potential across perforations at this disruption would break the hydrogen bonds securing the gB fusion loops, leading to fusion of the plasma and viral membranes. This mechanism agrees with the high stability of the tall trimeric spike structure of gB and is consistent with the probable existence of a more compact initial conformation that would allow it to closely approach the plasma membrane. The release of the fusion domains by disruption of hydrogen bonds is shared with the endocytotic entry pathway where, for some cell types not punctured by gB, the virus is able to induce inward forces that cause endocytosis and the fusion loops are released by acidification. The puncture fusion mechanism requires low critical strain or high tissue strain, matching primary tropism of neural processes at the vermillion border. In support of this mechanism, this paper proposes a functional superstructure of the antigens essential to entry and reviews its consistency with experimental evidence. PMID- 27617924 TI - Border Control in Hepatitis C Virus Infection: Inhibiting Viral Entry. AB - A new era has begun in the treatment of hepatitis C virus (HCV) infection with powerful yet expensive therapies. New treatments are emerging that target the entry step of HCV and could potentially block reinfection after liver transplant. These treatments include antibodies, which target the virus or host receptors required by HCV. Additionally, several new and previously approved small-molecule compounds have been described that target unique aspects of HCV entry. Overall, the blocking entry represents an attractive strategy that could yield powerful combination therapies to combat HCV. PMID- 27617925 TI - Targeting Viral Entry for Treatment of Hepatitis B and C Virus Infections. AB - Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections remain major health problems worldwide, with 400-500 million chronically infected people worldwide. Chronic infection results in liver cirrhosis and hepatocellular carcinoma, the second leading cause of cancer death. Current treatments for HBV limit viral replication without efficiently curing infection. HCV treatment has markedly progressed with the licensing of direct-acting antivirals (DAAs) for HCV cure, yet limited access for the majority of patients is a major challenge. Preventative and curative treatment strategies, aimed at novel targets, are needed for both viruses. Viral entry represents one such target, although detailed knowledge of the entry mechanisms is a prerequisite. For HBV, the recent discovery of the NTCP cell entry factor enabled the establishment of an HBV cell culture model and showed that cyclosporin A and Myrcludex B are NTCP-targeting entry inhibitors. Advances in the understanding of HCV entry revealed it to be a complex process involving many factors, offering several antiviral targets. These include viral envelope proteins E1 and E2, virion-associated lipoprotein ApoE, and cellular factors CD81, SRBI, EGFR, claudin-1, occludin, and the cholesterol transporter NPC1L1. Small molecules targeting SR-BI, EGFR, and NPC1L1 have entered clinical trials, whereas other viral- and host-targeted small molecules, peptides, and antibodies show promise in preclinical models. This review summarizes the current understanding of HBV and HCV entry and describes novel antiviral targets and compounds in different stages of clinical development. Overall, proof-of-concept studies indicate that entry inhibitors are a promising class of antivirals to prevent and treat HBV and HCV infections. PMID- 27617926 TI - Flavivirus Entry Inhibitors. AB - Many flaviviruses are significant human pathogens that are transmitted by mosquitoes and ticks. Although effective vaccines are available for yellow fever virus, Japanese encephalitic virus, and tick-borne encephalitis virus, these and other flaviviruses still cause thousands of human deaths and millions of illnesses each year. No clinically approved antiviral therapy is available for flavivirus treatment. To meet this unmet medical need, industry and academia have taken multiple approaches to develop antiflavivirus therapy, among which targeting viral entry has been actively pursued in the past decade. Here we review the current knowledge of flavivirus entry and its use for small molecule drug discovery. Inhibitors of two major steps of flaviviral entry have been reported: (i) molecules that block virus-receptor interaction; (ii) compounds that prevent conformational change of viral envelope protein during virus-host membrane fusion. We also discuss the advantages and disadvantages of targeting viral entry for treatment of flavivirus infection as compared to targeting viral replication proteins. PMID- 27617927 TI - Profiling Kinase Activity during Hepatitis C Virus Replication Using a Wortmannin Probe. AB - To complete its life cycle, the hepatitis C virus (HCV) induces changes to numerous aspects of its host cell. As kinases act as regulators of many pathways utilized by HCV, they are likely enzyme targets for virally induced inhibition or activation. Herein, we used activity-based protein profiling (ABPP), which allows for the identification of active enzymes in complex protein samples and the quantification of their activity, to identify kinases that displayed differential activity in HCV-expressing cells. We utilized an ABPP probe, wortmannin-yne, based on the kinase inhibitor wortmannin, which contains a pendant alkyne group for bioconjugation using bioorthogonal chemistry. We observed changes in the activity of kinases involved in the mitogen-activated protein kinase pathway, apoptosis pathways, and cell cycle control. These results establish changes to the active kinome, as reported by wortmannin-yne, in the proteome of human hepatoma cells actively replicating HCV. The observed changes include kinase activity that affect viral entry, replication, assembly, and secretion, implying that HCV is regulating the pathways that it uses for its life cycle through modulation of the active kinome. PMID- 27617928 TI - Magnetic molecularly imprinted composite for the selective solid-phase extraction of p-aminosalicylic acid followed by high-performance liquid chromatography with ultraviolet detection. AB - A new method for the selective extraction of p-aminosalicylic acid from aqueous and urine samples has been developed using magnetic molecularly imprinted polymer nanoparticles before determination by high-performance liquid chromatography. The Fe3 O4 nanoparticles were first prepared through the chemical coprecipitation of Fe2+ and Fe3+ and then coated with a vinyl shell. Subsequently, a layer of molecularly imprinted polymers was grafted onto the vinyl-modified magnetic nanoparticles by precipitation polymerization. FTIR spectroscopy, scanning electron microscopy, vibrating sample magnetometry, and thermogravimetric analysis were applied to characterize the sorbent properties. Moreover, the predominant parameters affecting the magnetic solid phase extraction such as sample pH, sorption and elution times, the amount of sorbent, and composition and volume of eluent were investigated thoroughly. The maximum sorption capacity of the imprinted polymer toward p-aminosalicylic acid was 70.9 mg/g, which is 4.5 times higher than that of the magnetic nonimprinted polymer. The magnetic molecularly imprinted polymer nanoparticles were applied for the selective extraction of p-aminosalicylic acid from aqueous and urine samples and satisfactory results were achieved. The results illustrate that magnetic molecularly imprinted polymer nanoparticles have a great potential in the extraction of p-aminosalicylic acid from environmental and biological matrices. PMID- 27617929 TI - Self-repair promotes microtubule rescue. AB - The dynamic instability of microtubules is characterized by slow growth phases stochastically interrupted by rapid depolymerizations called catastrophes. Rescue events can arrest the depolymerization and restore microtubule elongation. However, the origin of these rescue events remains unexplained. Here we show that microtubule lattice self-repair, in structurally damaged sites, is responsible for the rescue of microtubule growth. Tubulin photo-conversion in cells revealed that free tubulin dimers can incorporate along the shafts of microtubules, especially in regions where microtubules cross each other, form bundles or become bent due to mechanical constraints. These incorporation sites appeared to act as effective rescue sites ensuring microtubule rejuvenation. By securing damaged microtubule growth, the self-repair process supports a mechanosensitive growth by specifically promoting microtubule assembly in regions where they are subjected to physical constraints. PMID- 27617930 TI - Protein kinase C controls lysosome biogenesis independently of mTORC1. AB - Lysosomes respond to environmental cues by controlling their own biogenesis, but the underlying mechanisms are poorly understood. Here we describe a protein kinase C (PKC)-dependent and mTORC1-independent mechanism for regulating lysosome biogenesis, which provides insights into previously reported effects of PKC on lysosomes. By identifying lysosome-inducing compounds we show that PKC couples activation of the TFEB transcription factor with inactivation of the ZKSCAN3 transcriptional repressor through two parallel signalling cascades. Activated PKC inactivates GSK3beta, leading to reduced phosphorylation, nuclear translocation and activation of TFEB, while PKC activates JNK and p38 MAPK, which phosphorylate ZKSCAN3, leading to its inactivation by translocation out of the nucleus. PKC activation may therefore mediate lysosomal adaptation to many extracellular cues. PKC activators facilitate clearance of aggregated proteins and lipid droplets in cell models and ameliorate amyloid beta plaque formation in APP/PS1 mouse brains. Thus, PKC activators are viable treatment options for lysosome-related disorders. PMID- 27617931 TI - EB1 interacts with outwardly curved and straight regions of the microtubule lattice. AB - EB1 is a microtubule plus-end tracking protein that recognizes GTP-tubulin dimers in microtubules and thus represents a unique probe to investigate the architecture of the GTP cap of growing microtubule ends. Here, we conjugated EB1 to gold nanoparticles (EB1-gold) and imaged by cryo-electron tomography its interaction with dynamic microtubules assembled in vitro from purified tubulin. EB1-gold forms comets at the ends of microtubules assembled in the presence of GTP, and interacts with the outer surface of curved and straight tubulin sheets as well as closed regions of the microtubule lattice. Microtubules assembled in the presence of GTP, different GTP analogues or cell extracts display similarly curved sheets at their growing ends, which gradually straighten as their protofilament number increases until they close into a tube. Together, our data provide unique structural information on the interaction of EB1 with growing microtubule ends. They further offer insights into the conformational changes that tubulin dimers undergo during microtubule assembly and the architecture of the GTP-cap region. PMID- 27617933 TI - Hepatitis E in decompensated alcoholic cirrhosis. PMID- 27617935 TI - Do non-melanoma skin cancer survivors use tanning beds less often than the general public? AB - Purpose Indoor tanning is associated with an increased risk of non-melanoma skin cancers (NMSC), yet little is known about indoor tanning habits of individuals with a history of NMSC. Methods We examined self-reported history of NMSC and tanning bed use among non-Hispanic white respondents in the 2010 National Health Interview Survey (NHIS), a cross-sectional population-based survey designed to be representative of the civilian US population. We computed weighted population estimates and standard errors using the Taylor series linearization method. We then evaluated chi-square tests of independence and conducted weighted logistic regression analyses to evaluate if NMSC status was a predictor of indoor tanning. Results In our analytic sample of 14,400 non-Hispanic white participants, representing 145,287,995 in the population, 543 participants (weighted proportion = 3.45%) self-reported a history of NMSC or "skin cancer type not known." In multivariate analyses, non-melanoma skin cancer survivors were no less likely to use tanning beds in the last 12 months than skin cancer free controls (OR = 0.70, 95% CI: 0.34-1.43, p = 0.33). Conclusions Non-melanoma skin cancer survivors should be educated on their increased risk of recurrence and other skin cancers and in particular the role of indoor tanning in skin tumorigenesis. PMID- 27617934 TI - Comparing the efficacies of alginate, foam, hydrocolloid, hydrofiber, and hydrogel dressings in the management of diabetic foot ulcers and venous leg ulcers: a systematic review and meta-analysis examining how to dress for success. AB - Diabetic foot ulcers and venous leg ulcers are chronic wounds frequently encountered by dermatologists. Choosing appropriate wound dressings can effectively promote wound healing and potentially reduce morbidity and financial burden experienced by patients. The objective of our systematic review and meta analysis was to evaluate wound healing efficacies of synthetic active dressings in diabetic foot ulcer and venous leg ulcer management. For data collection, PubMed, Embase, Cochrane Library, CINAHL, and clinicaltrials.gov online databases were searched from database inception to 10 May 2015. Fixed and random effects modeling were used to calculate pooled risk ratios for complete ulcer healing from pairwise dressing comparisons. The results of our review showed moderate quality level evidence that hydrogels were more effective in healing diabetic foot ulcers than basic wound contact dressings (RR 1.80 [95% CI, 1.27-2.56]). The other dressing comparisons showed no statistically significant differences between the interventions examined in terms of achieving complete diabetic foot ulcer healing. Non-adherent dressings were more cost-effective than hydrofiber dressings for diabetic foot ulcers in terms of mean total cost per patient of the dressings themselves. All venous leg ulcer pairwise dressing comparisons showed equivalent dressing efficacies in terms of promoting complete ulcer healing. Overall, most synthetic active dressings and traditional wound dressings are equally efficacious in treating diabetic foot ulcers and venous leg ulcers. For treating diabetic foot ulcers, hydrogels are more efficacious than basic wound contact dressings, and non-adherent dressings are more cost-effective than hydrofiber dressings. Ultimately, dressing choice should be tailored to the wound and the patient. PMID- 27617936 TI - Generalized eruptive histiocytosis associated with a novel fusion in LMNA-NTRK1. AB - Non-Langerhans cell histiocytosis (NLCH) is a histiocyte disorder comprised of dermal dendritic histiocytes with a characteristic staining pattern. Erdheim Chester disease (ECD) is a subset of NLCH in which patients experience bone pain with corresponding changes on imaging. In addition, these patients show other evidence of systemic involvement, which can also be identified with imaging. This disease can occasionally present with cutaneous findings. We present a case of generalized eruptive histiocytosis (GEH), misdiagnosed as ECD, found to have an NTRK1 gene rearrangement. This is the first report of an NTRK1 kinase fusion with NLCH. The implication is unclear and further studies are warranted. PMID- 27617932 TI - Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. AB - Poorly organized tumour vasculature often results in areas of limited nutrient supply and hypoxia. Despite our understanding of solid tumour responses to hypoxia, how nutrient deprivation regionally affects tumour growth and therapeutic response is poorly understood. Here, we show that the core region of solid tumours displayed glutamine deficiency compared with other amino acids. Low glutamine in tumour core regions led to dramatic histone hypermethylation due to decreased alpha-ketoglutarate levels, a key cofactor for the Jumonji-domain containing histone demethylases. Using patient-derived (V600E)BRAF melanoma cells, we found that low-glutamine-induced histone hypermethylation resulted in cancer cell dedifferentiation and resistance to BRAF inhibitor treatment, which was largely mediated by methylation on H3K27, as knockdown of the H3K27-specific demethylase KDM6B and the methyltransferase EZH2 respectively reproduced and attenuated the low-glutamine effects in vitro and in vivo. Thus, intratumoral regional variation in the nutritional microenvironment contributes to tumour heterogeneity and therapeutic response. PMID- 27617937 TI - Recurrent adult onset Henoch-Schonlein Purpura: a case report. AB - Henoch-Schonlein purpura is an immunoglobulin A (IgA)-immune complex mediated leukocytoclastic vasculitis that classically manifests with palpable purpura, abdominal pain, arthritis, and hematuria or proteinuria. The condition is much more predominant in children (90% of cases) and commonly follows an upper respiratory infection. We present a case of recurrent Henoch-Schonlein purpura (HSP) complicated by nephritis in an adult female initially categorized as IgA nephropathy (IgAN). We review the pathophysiologic basis of HSP nephritis as the variant of HSP accompanied by renal involvement and its pathogenetic commonality with IgA nephropathy. PMID- 27617938 TI - Treatment of rosacea with topical ivermectin cream: a series of 34 cases. AB - Rosacea is a highly prevalent, chronic inflammatory disease. The use of topical ivermectin cream has recently been described in the treatment of rosacea in three clinical trials. We report our experience in a series of 34 patients treated with topical ivermectin cream. The results are a reflection of the reality of clinical practice and the perception of patients of the treatment. We also evaluate the efficacy in cases of mild rosacea and erythematotelangiectatic rosacea which have not been studied in trials. PMID- 27617939 TI - Fluoroscopy-induced radionecrosis. AB - Complications from radiation exposure during fluoroscopic guidance of cardiac catheterization may occur. With repeated procedures, the risk for cutaneous injuries increases. Herein, we describe a 59-year-old man with extensive coronary artery disease, who had undergone multiple revascularization procedures and developed a non-healing ulcer on his left inferior scapula. The patient's medical history, physical exam findings, and histopathology gave clues to a case of radiation-induced dermatitis and necrosis. PMID- 27617940 TI - Nilontinib induced keratosis pilaris atrophicans. AB - Keratosis pilaris (KP) is a disorder of follicular keratinization that is characterized by keratin plugs in the hair follicles with surrounding erythema. A 46-year-old man with chronic myelogenous leukemia (CML) was started on nilotinib, a second generation tyrosine kinase inhibitor (TKI). Two months later the patient noticed red bumps on the skin and patchy hair loss on the arms, chest, shoulders, back, and legs. Cutaneous reactions to nilotinib are the most frequent non hematologic adverse effects reported. However, it is important to distinguish KP like eruptions from more severe drug hypersensitivity eruptions, which can necessitate discontinuing the medication. Also, it is important to classify the cutaneous eruptions in patients on TKI according to the morphology instead of labeling them all as "chemotherapy eruption" to be able to better manage these adverse effects. PMID- 27617941 TI - Epithelioid angiosarcoma of the skin. A malignant tumor mimicking many different neoplasms. AB - Epithelioid angiosarcomas are rare malignant mesenchymal tumors. The main problem of these tumors is the complicate clinical and histological diagnosis. We report a case with an immunohistochemical panel. We propose the use of CD31 in the immunohistochemical panel of an undifferenciated tumor with epithelioid features, because it appears to be the only endothelial marker these tumors constantly express. PMID- 27617942 TI - Mucin in the dermis: a case of tender tumors. AB - We present an original case report of a 45-year-old woman with a five-month history of sporadic, tender, nodules present on the right upper abdomen, bilateral dorsal wrists, right upper arm, and left flank. Biopsy revealed a mild perivascular infiltrate, increased dermal mucin, and no significant increase in fibroblasts. Presentation and histology were most consistent with nodular lichen myxedematosus (NLM), a rare primary mucinosis. Only four previous cases are reported in the literature to our knowledge. Management of NLM and other subtypes of lichen myxedematosus is not well described. Our patient failed systemic steroids and was unable to tolerate hydroxychloroquine, but subsequently improved with oral methotrexate. This suggests that methotrexate may be of benefit for NLM. PMID- 27617943 TI - Frictional alopecia of the distal legs: case series and review. AB - BackgroundAcquired alopecia of the lower legs may occur secondary to friction due to socks, footwear, or both on the lower extremities. There is scant literature that reports on this phenomenon.Methods and MaterialsWe describe 5 patients who presented with alopecia of their lower legs induced by socks, footwear, or both. METHODS AND MATERIALS: We reviewed PubMed for the following terms: ankle alopecia, friction alopecia, frictional alopecia, lower extremity alopecia, non scarring leg alopecia, and sock alopecia. We also reviewed papers containing these terms and their references.ResultsAcquired frictional alopecia of the lower extremities is often an asymptomatic condition found incidentally on physical examination. The condition can persist for many years despite removal of the source of friction.ConclusionThe incidence of acquired frictional alopecia of the lower extremities may be greater than reflected in previously published reports. It is a non-scarring subtype of alopecia that was noted as an incidental finding during the patient's dermatology appointment. PMID- 27617944 TI - Primary periungual leiyomyosarcoma. AB - Primary superficial leiomyosarcoma is a very uncommon malignant tumor which occurs most commonly the lower limbs. We report one case of unusual topography of this tumor. An 81-year-old female patient presented with a 2 year history of a periungual tumor of the left index finger. The histopathological and immunohistochemical examination of a biopsy specimen was compatible with the diagnosis of leiomyosarcoma. There was no evidence of metastatic disease. An amputation of the index was performed. PMID- 27617945 TI - Erythematous papules over the neck: a diagnostic conundrum. AB - Syringomas are common appendageal neoplasms, manifested as skin-colored papules, most commonly distributed over the periorbital region. We describe a patient with syringoma localized over the neck and upper chest. PMID- 27617946 TI - A case of pachydermodactyly in a seventeen year old associated with repetitive minor trauma. AB - A boy presented initially to a Rheumatology clinic with a three year history of asymptomatic swelling of the third to fourth proximal interphalangeal (PIP) joints bilaterally. A presumptive diagnosis of seronegative arthritis was made. Sulfasalazine was commenced without improvement and resulted in mood disturbance. Blood tests including ESR, lupus anticoagulant, rheumatoid factor and CCP antibodies were unremarkable. Hand radiographs were normal. MRI showed oedema within soft tissues around PIP joints. His care was transferred to the Rheumatology unit in our hospital and the rheumatological diagnosis was revised; sulfasalazine was stopped and skin biopsy organised. Onward referral to Dermatology was made. Examination revealed symmetrical swelling and thickening of soft tissues on PIP joints with no evidence of joint synovitis. He denied habitual behaviour but was noted to rub his fingers subconsciously. With this as a cause of repetitive minor trauma, a clinical diagnosis of pachydermodactyly was made. Skin biopsy was supportive showing a dermis with coarse collagen. Pachydermodactyly is rare. This case highlights the importance of prompt recognition to avoid invasive and excessive diagnostic procedures as well as unnecessary immunosuppression. PMID- 27617947 TI - External ear nodule revealing a disseminated Kaposi disease. AB - Kaposi disease (KD) is an angiogenetic tumor process, characterized by its various clinical aspects. Its pathogenesis is multifactorial and it was attributed to HHV-8 infection. We report an original case of disseminated KD revealed by solitary lesion of external ear in a patient treated by corticosteroids for bullous pemphigoid. PMID- 27617948 TI - Top-cited psoriasis authors in 4 high-impact dermatology journals: 2000-2012. AB - Psoriasis is a largely researched topic with abundant potential for publication in dermatologic journals. We used the Thomson Reuters' Web of Science citation database using the search term "psoriasis" in the titles of any literature published in 4 high-impact dermatology journals. We compiled a ranking of the top 25 cited first authors and top 25 cited authors overall on the subject of psoriasis between 2000-2012. We hope our analysis highlights the achievements of our colleagues and predecessors. PMID- 27617949 TI - Active tuberculosis in a psoriasis patient treated with tumor necrosis factor inhibitors despite an initial negative tuberculin skin test and no known risk factors. AB - Tumor necrosis factor (TNF) inhibitors are becoming more common in the treatment of moderate-to-severe chronic plaque psoriasis. These medications have a low incidence of serious adverse events and are generally considered safe; however, they do make patients more susceptible to tuberculosis (TB) infection both through latent reactivation and primary infection. We describe a case of a patient who had an initial negative tuberculin skin test (TST), began TNF inhibitor therapy, and then 11 years later was diagnosed with active TB. After the initial screening, the patient did not have any subsequent screenings for TB and no apparent change to his TB risk status. TB is still common in many areas of the United States and travel is not necessary to be exposed. Patients on TNF inhibitors that develop active TB have increased morbidity and mortality than those who are not. It is necessary that dermatologists limit the risk of TB to patients by screening them before initiation and annually when they are on the TNF inhibitor. PMID- 27617950 TI - Uremic pruritus treated successfully with the Goeckerman Program. AB - Uremic pruritus (UP) is a common condition among patients with chronic kidney disease (CKD) on hemodialysis (HD). We report 19 a case of severe UP recalcitrant to conventional therapy including topical corticosteroids, anti-histamines, and phototherapy, 20 which was treated successfully with the Goeckerman regimen consisting of topical coal tar, topical corticosteroids, and broadband 21 UVB (BB UVB). Little is known about the pathophysiology of UP, and there is currently no consensus or evidence-based 22 treatments for UP. Although further studies are necessary, Goeckerman therapy may be a promising treatment option when 23 available for severe UP intractable to conventional therapies. PMID- 27617952 TI - UNIVERSITY OF CALIFORNIA HEALTH SYSTEM SCHOOL OF MEDICINE DEPARTMENT OF DERMATOLOGY. PMID- 27617951 TI - Zebrafish for modeling skin disorders. AB - The experimental advantages of zebrafish make this model system highly amenable to the field of dermatology. Zebrafish skin development is similar to humans and its genome is ~70% orthologous to the human genome. Its external developmental process allows for genetic manipulation and analysis of embryogenesis within a short time frame with all important internal organs and skin compartments formed within 6 days. Zebrafish models of cutaneous human diseases offer insight into pathogenesis and a unique platform for testing of potential therapies. This review details the specific advantages of zebrafish and highlights its use in dermatological research. PMID- 27617953 TI - Cytotoxic Ceanothane- and Lupane-Type Triterpenoids from the Roots of Ziziphus jujuba. AB - Ziziphus jujuba, a plant in the family Rhamnaceae, is used in several Asian countries as a food and traditional medicine. Fifteen new ceanothane-type (1-15) and three new lupane-type triterpenoids (16-18) were isolated from the roots of Z. jujuba, as well as 12 previously known triterpenoids (19-30). Their structures were elucidated by 1D and 2D NMR spectroscopic and HR mass spectrometric data analysis. Compounds 12 and 13 were found to possess a rare E-ring gamma-lactone structure, and 14 was assigned as the first 2,28-dinorlupane derivative isolated as a natural product. Twenty-five of the isolates were examined for cytotoxicity against human hepatocellular carcinoma HepG2 cells, and compounds 6-8, 14, 17, 23, 25, 29, and 30 showed cytotoxicity with IC50 values ranging from 1.9 to 5.9 MUM. PMID- 27617954 TI - Influence of the Selectivity Filter Properties on Proton Selectivity in the Influenza A M2 Channel. AB - The homotetrameric M2 proton channel of influenza A plays a crucial role in the viral life cycle and is thus an important therapeutic target. It selectively conducts protons against a background of other competing cations whose concentrations are up to a million times greater than the proton concentration. Its selectivity is largely determined by a constricted region of its open pore known as the selectivity filter, which is lined by four absolutely conserved histidines. While the mechanism of proton transport through the channel has been studied, the physical principles underlying the selectivity for protons over other cations in the channel's His4 selectivity filter remain elusive. Furthermore, it is not known if proton selectivity absolutely requires all four histidines with two of the four histidines protonated and if other titratable amino acid residues in lieu of the histidines could bind protons and how they affect proton selectivity. Here, we elucidate how the competition between protons and rival cations such as Na+ depends on the selectivity filter's (1) histidine protonation state, (2) solvent exposure, (3) oligomeric state (the number of protein chains and thus the number of His ligands), and (4) ligand composition by evaluating the free energies for replacing monovalent Na+ with H3O+ in various model selectivity filters. We show that tetrameric His4 filters are more proton selective than their trimeric His3 counterparts, and a dicationic His4 filter where two of the four histidines are protonated is more proton-selective than tetrameric filters with other charge states/composition (different combinations of His protonation states or different metal-ligating ligands). The [His4]2+ filter achieves proton selectivity by providing suboptimal binding conditions for rival cations such as Na+, which prefers a neutral or negatively charged filter instead of a dicationic one, and three rather than four ligands with oxygen ligating atoms. PMID- 27617958 TI - Probe-Based Confocal Laser Endomicroscopy for Imaging TRAIL-Expressing Mesenchymal Stem Cells to Monitor Colon Xenograft Tumors In Vivo. AB - INTRODUCTION: Mesenchymal stem cells (MSCs) can serve as vehicles for therapeutic genes. However, little is known about MSC behavior in vivo. Here, we demonstrated that probe-based confocal laser endomicroscopy (pCLE) can be used to track MSCs in vivo and individually monitor tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) gene expression within carcinomas. METHODS: Isolated BALB/c nu/nu mice MSCs (MSCs) were characterized and engineered to co-express the TRAIL and enhanced green fluorescent protein (EGFP) genes. The number of MSCs co expressing EGFP and TRAIL (TRAIL-MSCs) at tumor sites was quantified with pCLE in vivo, while their presence was confirmed using immunofluorescence (IF) and quantitative polymerase chain reaction (qPCR). The therapeutic effects of TRAIL MSCs were evaluated by measuring the volumes and weights of subcutaneous HT29 derived xenograft tumors. RESULTS: Intravital imaging of the subcutaneous xenograft tumors revealed that BALB/c mice treated with TRAIL-MSCs exhibited specific cellular signals, whereas no specific signals were observed in the control mice. The findings from the pCLE images were consistent with the IF and qPCR results. CONCLUSION: The pCLE results indicated that endomicroscopy could effectively quantify injected MSCs that homed to subcutaneous xenograft tumor sites in vivo and correlated well with the therapeutic effects of the TRAIL gene. By applying pCLE for the in vivo monitoring of cellular trafficking, stem cell based anticancer gene therapeutic approaches might be feasible and attractive options for individualized clinical treatments. PMID- 27617959 TI - Forsythoside A Inhibits BVDV Replication via TRAF2-Dependent CD28-4-1BB Signaling in Bovine PBMCs. AB - Bovine viral diarrhea virus (BVDV), the causative agent of bovine viral diarrhea/mucosal disease (BVD/MD), is an important pathogen of cattle and other wild animals throughout the world. BVDV infection typically leads to an impaired immune response in cattle. In the present study, we investigated the effect of Forsythoside A (FTA) on BVDV infection of bovine peripheral blood mononuclear cells (PBMCs). We found that Forsythoside A could not only promote proliferation of PBMCs and T cells activation but also inhibit the replication of BVDV as well as apoptosis induced by BVDV. FTA treatment could counteract the BVDV-induced overproduction of IFN-gamma to maintain the immune homeostasis in bovine PBMCs. At same time, FTA can enhance the secretion of IL-2. What's more, BVDV promotes the expression of CD28, 4-1BB and TRAF-2, which can be modulated by FTA. Our data suggest that FTA protects PBMCs from BVDV infection possibly via TRAF2-dependent CD28-4-1BB signaling, which may activate PBMCs in response to BVDV infection. Therefore, this aids in the development of an effective adjuvant for vaccines against BVDV and other specific FTA-based therapies for preventing BVDV infection. PMID- 27617960 TI - Evidence of Flicker-Induced Functional Hyperaemia in the Smallest Vessels of the Human Retinal Blood Supply. AB - Regional changes in blood flow are initiated within neural tissue to help fuel local differences in neural activity. Classically, this response was thought to arise only in larger arterioles and venules. However, recently, it has been proposed that a) the smallest vessels of the circulation make a comparable contribution, and b) the response should be localised intermittently along such vessels, due to the known distribution of contractile mural cells. To assess these hypotheses in human neural tissue in vivo, we imaged the retinal microvasculature (diameters 3-28 MUm) non-invasively, using adaptive optics, before and after delivery of focal (360 MUm) patches of flickering visible light. Our results demonstrated a definite average response in 35% of all vessel segments analysed. In these responding vessels, the magnitude of proportional dilation (mean +/- SEM for pre-capillary arterioles 13 +/- 5%, capillaries 31 +/- 8%, and post-capillary venules 10 +/- 3%) is generally far greater than the magnitudes we and others have measured in the larger retinal vessels, supporting proposition a) above. The dilations observed in venules were unexpected based on previous animal work, and may be attributed either to differences in stimulus or species. Response heterogeneity across the network was high; responses were also heterogeneous along individual vessels (45% of vessel segments showed demonstrable locality in their response). These observations support proposition b) above. We also observed a definite average constriction across 7% of vessel segments (mean +/- SEM constriction for capillaries -16 +/- 3.2%, and post capillary venules -18 +/- 12%), which paints a picture of dynamic redistribution of flow throughout the smallest vessel networks in the retina in response to local, stimulus-driven metabolic demand. PMID- 27617961 TI - The PU.1-Modulated MicroRNA-22 Is a Regulator of Monocyte/Macrophage Differentiation and Acute Myeloid Leukemia. AB - MicroRNA-22 (miR-22) is emerging as a critical regulator in organ development and various cancers. However, its role in normal hematopoiesis and leukaemogenesis remains unclear. Here, we detected its increased expression during monocyte/macrophage differentiation of HL-60, THP1 cells and CD34+ hematopoietic stem/progenitor cells, and confirmed that PU.1, a key transcriptional factor for monocyte/macrophage differentiation, is responsible for transcriptional activation of miR-22 during the differentiation. By gain- and loss-of-function experiments, we demonstrated that miR-22 promoted monocyte/macrophage differentiation, and MECOM (EVI1) mRNA is a direct target of miR-22 and MECOM (EVI1) functions as a negative regulator in the differentiation. The miR-22 mediated MECOM degradation increased c-Jun but decreased GATA2 expression, which results in increased interaction between c-Jun and PU.1 via increasing c-Jun levels and relief of MECOM- and GATA2-mediated interference in the interaction, and thus promoting monocyte/macrophage differentiation. We also observed significantly down-regulation of PU.1 and miR-22 as well as significantly up regulation of MECOM in acute myeloid leukemia (AML) patients. Reintroduction of miR-22 relieved the differentiation blockage and inhibited the growth of bone marrow blasts of AML patients. Our results revealed new function and mechanism of miR-22 in normal hematopoiesis and AML development and demonstrated its potential value in AML diagnosis and therapy. PMID- 27617964 TI - Using Broken Windows Theory as the Backdrop for a Proactive Approach to Threat Identification in Health Care. AB - OBJECTIVES: Historically, health care has relied on error management techniques to measure and reduce the occurrence of adverse events. This study proposes an alternative approach for identifying and analyzing hazardous events. Whereas previous research has concentrated on investigating individual flow disruptions, we maintain the industry should focus on threat windows, or the accumulation of these disruptions. This methodology, driven by the broken windows theory, allows us to identify process inefficiencies before they manifest and open the door for the occurrence of errors and adverse events. METHODS: Medical human factors researchers observed disruptions during 34 trauma cases at a Level II trauma center. Data were collected during resuscitation and imaging and were classified using a human factors taxonomy: Realizing Improved Patient Care Through Human Centered Operating Room Design for Threat Window Analysis (RIPCHORD-TWA). RESULTS: Of the 576 total disruptions observed, communication issues were the most prevalent (28%), followed by interruptions and coordination issues (24% each). Issues related to layout (16%), usability (5%), and equipment (2%) comprised the remainder of the observations. Disruptions involving communication issues were more prevalent during resuscitation, whereas coordination problems were observed more frequently during imaging. CONCLUSIONS: Rather than solely investigating errors and adverse events, we propose conceptualizing the accumulation of disruptions in terms of threat windows as a means to analyze potential threats to the integrity of the trauma care system. This approach allows for the improved identification of system weaknesses or threats, affording us the ability to address these inefficiencies and intervene before errors and adverse events may occur. PMID- 27617962 TI - Calibration and Validation of a Wrist- and Hip-Worn Actigraph Accelerometer in 4 Year-Old Children. AB - INTRODUCTION: To determine time spent at different physical activity intensities, accelerometers need calibration. The aim of this study was to develop and cross validate intensity thresholds for the Actigraph GT3X+ accelerometer for wrist and hip placement in four-year-old children. METHODS: In total 30 children (49 months, SD 3.7) were recruited from five preschools in Stockholm. Equipped with an accelerometer on the wrist and another on the hip, children performed three indoor activities and one free-play session while being video recorded. Subsequently, physical activity intensity levels were coded every 5th second according to the Children's Activity Rating Scale. Receiver Operating Characteristic (ROC) curves was used to develop wrist and hip intensity thresholds, the upper threshold for sedentary, and lower threshold for moderate to-vigorous physical activity (MVPA), for the vertical axis (VA) and for the vector magnitude (VM). A leave-one-out method was used to cross-validate the thresholds. RESULTS: Intensity thresholds for wrist placement were <= 178 (VA) and <= 328 (VM) for sedentary and >= 871 (VA) and >= 1393 (VM) counts/5 seconds for MVPA. The corresponding thresholds for hip placement were <= 43 (VA) and <= 105 (VM) for sedentary and >= 290 (VA) and >= 512 (VM) for MVPA. The quadratic weighted Kappa was 0.92 (95% CI 0.91-0.93) (VA) and 0.95 (95% CI 0.94-0.96) (VM) for the wrist-worn accelerometer and 0.76 (98% CI 0.74-0.77) and 0.86 (95% CI 0.85-0.87) for the hip-worn. CONCLUSION: Using wrist placement and the VM when measuring physical activity with accelerometry in 4-year-old children is recommended. PMID- 27617963 TI - Improving Incident Reporting Among Physician Trainees. AB - BACKGROUND: Preventable medical harm is a leading cause of death in the United States. Incident reporting systems have been identified as the primary method to capture medical error and harm. Incidents are rarely reported, particularly among physician trainees. METHODS: We conducted a single-center, quasi-experimental study to examine the effect of education on the importance of and how to file an incident report for physician trainees on reporting rates. Trainees were provided laminated plastic instructions, and reporting was reinforced with weekly patient safety rounds. In addition, trainees completed anonymous surveys preintervention and postintervention to determine barriers to reporting. A chi test compared the number of reports preintervention and postintervention. RESULTS: For 6 months, 73 resident physicians participated in the study. Median incident reports entered by trainees increased from 1 report per month during the preintervention period to 10 reports per month after the intervention (P = 0.005). The most common barriers to reporting incidents before intervention were not knowing how to report (72.6%), what to report (56.2%), and lack of time (42.5%). A total of 13.7% reported fear of retaliation. Most incident reports were due to delay in patient care (40.9%) and medical errors (33.3%). CONCLUSIONS: Real-time education and regular reinforcement increased incident reporting among resident physicians. This educational approach may increase incidence reporting in other institutions. PMID- 27617965 TI - Variations in Patient Safety Climate in Chinese Hospitals. AB - OBJECTIVES: Patient safety climate is associated with patient outcomes in hospitals around the world. A better understanding of how safety climate varies within and across hospitals will help identify improvement opportunities. We examined variations in safety climate by work area and job category in Chinese hospitals. METHODS: We administered the Chinese Hospital Survey on Patient Safety Climate in 2011 to workers in 6 hospitals in China, with completed surveys from 1464 (86% response). We calculated the percent positive response for survey items and dimensions among hospitals and compared this across work areas and job categories using general linear models. RESULTS: Overall, 68% of responses suggested the presence of a positive safety climate. The percent positive responses were highest for organizational learning (86.1%) and unit management support for safety (84.5%) and lowest for staffing (30.6%) and error reporting (44.5%). Workers in surgical units, intensive care units, operating rooms, and emergency departments were slightly more negative regarding overall safety climate than those in medical and ancillary units. Physicians reported worse perceptions than nurses or other hospital workers on all dimensions except for unit management support for safety and communication and peer support. CONCLUSIONS: The perceived problem with staffing in Chinese hospitals was consistent with other studies. The lack of positive responses for error reporting may indicate a lack of awareness of the importance of learning from and reporting minor events and near misses. Variations within and across hospitals in safety climate suggest that improvement interventions should be tailored to individual units and professional groups. PMID- 27617966 TI - Anti-Ephrin Type-B Receptor 2 (EphB2) and Anti-Three Prime Histone mRNA EXonuclease 1 (THEX1) Autoantibodies in Scleroderma and Lupus. AB - In a pilot ProtoArray analysis, we identified 6 proteins out of 9483 recognized by autoantibodies (AAb) from patients with systemic sclerosis (SSc). We further investigated the 6 candidates by ELISA on hundreds of controls and patients, including patients with Systemic Lupus Erythematosus (SLE), known for high sera reactivity and overlapping AAb with SSc. Only 2 of the 6 candidates, Ephrin type B receptor 2 (EphB2) and Three prime Histone mRNA EXonuclease 1 (THEX1), remained significantly recognized by sera samples from SSc compared to controls (healthy or with rheumatic diseases) with, respectively, 34% versus 14% (P = 2.10-4) and 60% versus 28% (P = 3.10-8). Above all, EphB2 and THEX1 revealed to be mainly recognized by SLE sera samples with respectively 56%, (P = 2.10-10) and 82% (P = 5.10-13). As anti-EphB2 and anti-THEX1 AAb were found in both diseases, an epitope mapping was realized on each protein to refine SSc and SLE diagnosis. A 15-mer peptide from EphB2 allowed to identify 35% of SLE sera samples (N = 48) versus only 5% of any other sera samples (N = 157), including SSc sera samples. AAb titers were significantly higher in SLE sera (P<0.0001) and correlated with disease activity (p<0.02). We could not find an epitope on EphB2 protein for SSc neither on THEX1 for SSc or SLE. We showed that patients with SSc or SLE have AAb against EphB2, a protein involved in angiogenesis, and THEX1, a 3'-5' exoribonuclease involved in histone mRNA degradation. We have further identified a peptide from EphB2 as a specific and sensitive tool for SLE diagnosis. PMID- 27617969 TI - Functions, Regulation, and Therapeutic Implications of the ATR Checkpoint Pathway. AB - The ATR (ATM and rad3-related) pathway is crucial for proliferation, responding to DNA replication stress and DNA damage. This critical signaling pathway is carefully orchestrated through a multistep process requiring initial priming of ATR prior to damage, recruitment of ATR to DNA damage lesions, activation of ATR signaling, and, finally, modulation of ATR activity through a variety of post translational modifications. Following activation, ATR functions in several vital cellular processes, including suppression of replication origin firing, promotion of deoxynucleotide synthesis and replication fork restart, prevention of double stranded DNA break formation, and avoidance of replication catastrophe and mitotic catastrophe. In many cancers, tumor cells have increased dependence on ATR signaling for survival, making ATR a promising target for cancer therapy. Tumor cells compromised in DNA repair pathways or DNA damage checkpoints, cells reliant on homologous recombination, and cells with increased replication stress are particularly sensitive to ATR inhibition. Understanding ATR signaling and modulation is essential to unraveling which tumors have increased dependence on ATR signaling as well as how the ATR pathway can best be exploited for targeted cancer therapy. PMID- 27617967 TI - Infant Directed Speech Enhances Statistical Learning in Newborn Infants: An ERP Study. AB - Statistical learning and the social contexts of language addressed to infants are hypothesized to play important roles in early language development. Previous behavioral work has found that the exaggerated prosodic contours of infant directed speech (IDS) facilitate statistical learning in 8-month-old infants. Here we examined the neural processes involved in on-line statistical learning and investigated whether the use of IDS facilitates statistical learning in sleeping newborns. Event-related potentials (ERPs) were recorded while newborns were exposed to12 pseudo-words, six spoken with exaggerated pitch contours of IDS and six spoken without exaggerated pitch contours (ADS) in ten alternating blocks. We examined whether ERP amplitudes for syllable position within a pseudo word (word-initial vs. word-medial vs. word-final, indicating statistical word learning) and speech register (ADS vs. IDS) would interact. The ADS and IDS registers elicited similar ERP patterns for syllable position in an early 0-100 ms component but elicited different ERP effects in both the polarity and topographical distribution at 200-400 ms and 450-650 ms. These results provide the first evidence that the exaggerated pitch contours of IDS result in differences in brain activity linked to on-line statistical learning in sleeping newborns. PMID- 27617968 TI - Changes in Men's Physical Activity and Healthy Eating Knowledge and Behavior as a Result of Program Exposure: Findings From the Workplace POWERPLAY Program. AB - BACKGROUND: The purpose of this study was to examine changes in physical activity and healthy eating knowledge and behaviors associated with the level of exposure to POWERPLAY, a men-centered workplace health promotion program. METHODS: This study is based on a quasi-experimental prepost design. Using a computer assisted telephone interview survey, data regarding program exposure and physical activity and health eating knowledge and behaviors were collected from men (N = 103) in 4 workplaces. RESULTS: Exposure scores were calculated and participants were categorized as having low (n = 54) or high exposure (n = 49) to POWERPLAY. Compared with the low exposure group, those reporting high exposure scored significantly higher on physical activity knowledge (F (1, 99) =14.17, P < .001, eta2 = .125) and health eating knowledge (F (1, 99) =14.37, P = .001, eta2 = .111). The high exposure group also reported significantly more minutes walked place to place (F (2, 206) = 3.91, P = .022, eta2 = .037) and on minutes walked for leisure (F (2, 230) = 3.08, P = .048, eta2 = .026). CONCLUSIONS: POWERPLAY shows significant promise as a workplace health promotion approach and may have an even greater impact when program exposure is augmented with environmental and policy changes. PMID- 27617970 TI - Evolution in the Cycles of Life. AB - The life cycles of eukaryotes alternate between haploid and diploid phases, which are initiated by meiosis and gamete fusion, respectively. In both ascomycete and basidiomycete fungi and chlorophyte algae, the haploid-to-diploid transition is regulated by a pair of paralogous homeodomain protein encoding genes. That a common genetic program controls the haploid-to-diploid transition in phylogenetically disparate eukaryotic lineages suggests this may be the ancestral function for homeodomain proteins. Multicellularity has evolved independently in many eukaryotic lineages in either one or both phases of the life cycle. Organisms, such as land plants, exhibiting a life cycle whereby multicellular bodies develop in both the haploid and diploid phases are often referred to as possessing an alternation of generations. We review recent progress on understanding the genetic basis for the land plant alternation of generations and highlight the roles that homeodomain-encoding genes may have played in the evolution of complex multicellularity in this lineage. PMID- 27617972 TI - Robust Yet Fragile: Expression Noise, Protein Misfolding, and Gene Dosage in the Evolution of Genomes. AB - The complex manner in which organisms respond to changes in their gene dosage has long fascinated geneticists. Oddly, although the existence of dominance implies that dosage reductions often have mild phenotypes, extra copies of whole chromosomes (aneuploidy) are generally strongly deleterious. Even more paradoxically, an extra copy of the genome is better tolerated than is aneuploidy. We review the resolution of this paradox, highlighting the roles of biochemistry, protein aggregation, and disruption of cellular microstructure in that explanation. Returning to life's curious combination of robustness and sensitivity to dosage changes, we argue that understanding how biological robustness evolved makes these observations less inexplicable. We propose that noise in gene expression and evolutionary strategies for its suppression play a role in generating dosage phenotypes. Finally, we outline an unappreciated mechanism for the preservation of duplicate genes, namely preservation to limit expression noise, arguing that it is particularly relevant in polyploid organisms. PMID- 27617973 TI - Sperm Meets Egg: The Genetics of Mammalian Fertilization. AB - Fertilization is the culminating event of sexual reproduction, which involves the union of the sperm and egg to form a single, genetically distinct organism. Despite the fundamental role of fertilization, the basic mechanisms involved have remained poorly understood. However, these mechanisms must involve an ordered schedule of cellular recognition events between the sperm and egg to ensure successful fusion. In this article, we review recent progress in our molecular understanding of mammalian fertilization, highlighting the areas in which genetic approaches have been particularly informative and focusing especially on the roles of secreted and cell surface proteins, expressed in a sex-specific manner, that mediate sperm-egg interactions. We discuss how the sperm interacts with the female reproductive tract, zona pellucida, and the oolemma. Finally, we review recent progress made in elucidating the mechanisms that reduce polyspermy and ensure that eggs normally fuse with only a single sperm. PMID- 27617975 TI - Construction of Highly Catalytic Porous TiOPC Nanocomposite Counter Electrodes for Dye-Sensitized Solar Cells. AB - Developing low-cost, durable, and highly catalytic counter electrode (CE) materials based on earth-abundant elements is essential for dye-sensitized solar cells (DSSCs). In this study, we report a highly active nanostructured compositional material, TiOPC, which contains titanium, oxygen, phosphorus, and carbon, for efficient CE in I3-/I- electrolyte. The TiOPC nanocomposites are prepared from carbon thermal transformation of TiP2O7 in an atmosphere of nitrogen at high temperature, and their catalytic performance is regulated by changing the carbon content in the nanocomposites. The TiOPC with appropriate 24.6 wt % carbon and porous structure exhibits an enhanced electrocatalytic activity in the reduction of I3-, providing a short-circuit current density of 16.64 mA cm-2, an open-circuit potential of 0.78 V, and an energy conversion efficiency of 8.65%. The photovoltaic performance of TiOPC CE-based DSSC is even superior to that of a Pt CE-based cell (13.80 mA cm-2, 0.79 V, and 6.66%). The enhanced catalytic activity of TiOPC is attributed to the presence of predominant Ti-O-P-C structure along with the continuous conductive carbon network and the porous structure. PMID- 27617971 TI - Transition Metals and Virulence in Bacteria. AB - Transition metals are required trace elements for all forms of life. Due to their unique inorganic and redox properties, transition metals serve as cofactors for enzymes and other proteins. In bacterial pathogenesis, the vertebrate host represents a rich source of nutrient metals, and bacteria have evolved diverse metal acquisition strategies. Host metal homeostasis changes dramatically in response to bacterial infections, including production of metal sequestering proteins and the bombardment of bacteria with toxic levels of metals. In response, bacteria have evolved systems to subvert metal sequestration and toxicity. The coevolution of hosts and their bacterial pathogens in the battle for metals has uncovered emerging paradigms in social microbiology, rapid evolution, host specificity, and metal homeostasis across domains. This review focuses on recent advances and open questions in our understanding of the complex role of transition metals at the host-pathogen interface. PMID- 27617977 TI - Letter from the editor. PMID- 27617979 TI - Corrigendum. PMID- 27617980 TI - Expanding the Range of Diagnosable Autoimmune Encephalopathies and Encephalomyelopathies. PMID- 27617976 TI - The small unicellular diazotrophic symbiont, UCYN-A, is a key player in the marine nitrogen cycle. AB - Microbial dinitrogen (N2) fixation, the nitrogenase enzyme-catalysed reduction of N2 gas into biologically available ammonia, is the main source of new nitrogen (N) in the ocean. For more than 50 years, oceanic N2 fixation has mainly been attributed to the activity of the colonial cyanobacterium Trichodesmium1,2. Other smaller N2-fixing microorganisms (diazotrophs)-in particular the unicellular cyanobacteria group A (UCYN-A)-are, however, abundant enough to potentially contribute significantly to N2 fixation in the surface waters of the oceans3-6. Despite their abundance, the contribution of UCYN-A to oceanic N2 fixation has so far not been directly quantified. Here, we show that in one of the main areas of oceanic N2 fixation, the tropical North Atlantic7, the symbiotic cyanobacterium UCYN-A contributed to N2 fixation similarly to Trichodesmium. Two types of UCYN A, UCYN-A1 and -A2, were observed to live in symbioses with specific eukaryotic algae. Single-cell analyses showed that both algae-UCYN-A symbioses actively fixed N2, contributing ~20% to N2 fixation in the tropical North Atlantic, revealing their significance in this region. These symbioses had growth rates five to ten times higher than Trichodesmium, implying a rapid transfer of UCYN-A fixed N into the food web that might significantly raise their actual contribution to N2 fixation. Our analysis of global 16S rRNA gene databases showed that UCYN-A occurs in surface waters from the Arctic to the Antarctic Circle and thus probably contributes to N2 fixation in a much larger oceanic area than previously thought. Based on their high rates of N2 fixation and cosmopolitan distribution, we hypothesize that UCYN-A plays a major, but currently overlooked role in the oceanic N cycle. PMID- 27617981 TI - Effects of Combined Vigorous Interval Training Program and Diet on Body Composition, Physical Fitness, and Physical Self-Perceptions Among Obese Adolescent Boys and Girls. AB - PURPOSE: This study examined the effects of a five-week intervention combining vigorous interval training (VIT) with diet among twenty-four obese adolescents. Fourteen girls and ten boys (aged 14-15) schooled in a pediatric rehabilitation center participated. METHODS: The VIT intensity was targeted and remained above 80% of maximal heart rate (HR) and over six kilocalories per minute. Pre- and postintervention measures were body composition (BMI, weight, body fat percentage), physical self-perceptions (PSP), physical fitness (6-min walking distance and work) and its associated physiological responses (HRpeak and blood lactate concentration). A series of two-way analyses of variance or covariance controlling for weight loss were used to examine the changes. RESULTS: Significant improvements were found in body composition, physical fitness and PSP (endurance, activity level, sport competence, global physical self-concept and appearance). In addition, boys presented higher levels of perceived strength and global physical self-concept than girls. Finally, there was a significant increase in perceived endurance, sport competence, and global physical self concept in girls only. CONCLUSION: This five-week VIT program combined with diet represents an effective means for improving body composition, physical fitness, and PSP in obese adolescents, the effects on PSP being larger among girls. PMID- 27617982 TI - Catechins Variously Affect Activities of Conjugation Enzymes in Proliferating and Differentiated Caco-2 Cells. AB - The knowledge of processes in intestinal cells is essential, as most xenobiotics come into contact with the small intestine first. Caco-2 cells are human colorectal adenocarcinoma that once differentiated, exhibit enterocyte-like characteristics. Our study compares activities and expressions of important conjugation enzymes and their modulation by green tea extract (GTE) and epigallocatechin gallate (EGCG) using both proliferating (P) and differentiated (D) caco-2 cells. The mRNA levels of the main conjugation enzymes were significantly elevated after the differentiation of Caco-2 cells. However, no increase in conjugation enzymes' activities in differentiated cells was detected in comparison to proliferating ones. GTE/EGCG treatment did not affect the mRNA levels of any of the conjugation enzymes tested in either type of cells. Concerning conjugation enzymes activities, GTE/EGCG treatment elevated glutathione S-transferase (GST) activity by approx. 30% and inhibited catechol-O methyltransferase (COMT) activity by approx. 20% in differentiated cells. On the other hand, GTE as well as EGCG treatment did not significantly affect the activities of conjugation enzymes in proliferating cells. Administration of GTE/EGCG mediated only mild changes of GST and COMT activities in enterocyte-like cells, indicating a low risk of GTE/EGCG interactions with concomitantly administered drugs. However, a considerable chemo-protective effect of GTE via the pronounced induction of detoxifying enzymes cannot be expected as well. PMID- 27617983 TI - Three Pairs of New Isopentenyl Dibenzo[b,e]oxepinone Enantiomers from Talaromyces flavus, a Wetland Soil-Derived Fungus. AB - Three pairs of new isopentenyl dibenzo[b,e]oxepinone enantiomers, (+)-(5S) arugosin K (1a), (-)-(5R)-arugosin K (1b), (+)-(5S)-arugosin L (2a), (-)-(5R) arugosin L (2b), (+)-(5S)-arugosin M (3a), (-)-(5R)-arugosin M (3b), and a new isopentenyl dibenzo[b,e]oxepinone, arugosin N (4), were isolated from a wetland soil-derived fungus Talaromyces flavus, along with two known biosynthetically related compounds 5 and 6. Among them, arugosin N (4) and 1,6,10-trihydroxy-8 methyl-2-(3-methyl-2-butenyl)-dibenz[b,e]oxepin-11(6H)-one (CAS: 160585-91-1, 5) were obtained as the tautomeric mixtures. The structures of isolated compounds were determined by detailed spectroscopic analysis. In addition, the absolute configurations of these three pairs of new enantiomers were determined by quantum chemical ECD calculations. PMID- 27617984 TI - Boronic Acid Group: A Cumbersome False Negative Case in the Process of Drug Design. AB - Herein we present, an exhaustive docking analysis considering the case of autotaxin (ATX). HA155, a small molecule inhibitor of ATX, is co-crystallized. In order to further extract conclusions on the nature of the bond formed between the ligands and the amino acid residues of the active site, density functional theory (DFT) calculations were undertaken. However, docking does not provide reproducible results when screening boronic acid derivatives and their binding orientations to protein drug targets. Based on natural bond orbital (NBO) calculations, the formed bond between Ser/Thr residues is characterized more accurately as a polar covalent bond instead of a simple nonpolar covalent one. The presented results are acceptable and could be used in screening as an active negative filter for boron compounds. The hydroxyl groups of amino acids are bonded with the inhibitor's boron atom, converting its hybridization to sp3. PMID- 27617985 TI - A Systematic Review on the Implication of Minerals in the Onset, Severity and Treatment of Periodontal Disease. AB - Periodontal disease is an inflammatory disease with high prevalence in adults that leads to destruction of the teeth-supporting tissues. Periodontal therapy has been traditionally directed at reduction of the bacterial load to a level that encourages health-promoting bacteria and maintenance of oral-hygiene. The role of nutrition in different chronic inflammatory diseases has been the subject of an increasing body of research in the last decades. In this sense, there has been an important increase in the volume of research on role of nutrition in periodontitis since the diet has known effects on the immune system and inflammatory cascades. Minerals play a key role in all these processes due to the multiple pathways where they participate. To clarify the role of the different minerals in the establishment, progression and/or treatment of this pathology, a systemically review of published literature cited in PubMed until May 2016 was conducted, which included research on the relationship of these elements with the onset and progression of periodontal disease. Among all the minerals, calcium dietary intake seems important to maintain alveolar bone. Likewise, dietary proportions of minerals that may influence its metabolism also can be relevant. Lastly, some observations suggest that all those minerals with roles in immune and/or antioxidant systems should be considered in future research. PMID- 27617986 TI - Pharmacokinetic Comparison of Scutellarin and Paeoniflorin in Sham-Operated and Middle Cerebral Artery Occlusion Ischemia and Reperfusion Injury Rats after Intravenous Administration of Xin-Shao Formula. AB - Xin-Shao formula is a folk remedy widely used in China to prevent and cure stroke. Cerebral ischemic reperfusion (I/R) injury often takes place during the treatment of stroke. Information about the pharmacokinetic behavior of the remedy under cerebral I/R injury conditions is lacking. The present study aimed to compare the pharmacokinetic properties of scutellarin and paeoniflorin, two major bioactive components of Xin-Shao formula, under physiological state in cerebral I/R injury rats. Neurobehavioral dysfunction was evaluated and cerebral infarcted volume was measured in middle cerebral artery occlusion I/R injury (MCAO) rats. Plasma samples were collected at various time points after a single dose (intravenous, i.v.) of Xin-Shao formula. The levels of plasma scutellarin and paeoniflorin at the designed time points were determined by a UPLC-MS/MS method, and drug concentration versus time plots were constructed to estimate pharmacokinetic parameters. Increase in terminal elimination half-life (t1/2z) and mean residence time (MRT(0-t)) of scutellarin as well as elevation in area under the plasma drug concentration-time curve from 0 h to the terminal time point (AUC(0-t)) and maximum plasma drug concentration (Cmax) of paeoniflorin, along with decreased clearance of paeoniflorin and scutellarin as well as reduced apparent volume of distribution (Vz) of paeoniflorin, were observed in MCAO rats, compared with those in sham-operated animals. The elimination of scutellarin and paeoniflorin were reduced in cerebral I/R injury reduced rats. PMID- 27617987 TI - Isolation of alpha-Amylase Inhibitors from Kadsura longipedunculata Using a High Speed Counter-Current Chromatography Target Guided by Centrifugal Ultrafiltration with LC-MS. AB - In this study, a high-speed counter-current chromatography (HSCCC) separation method target guided by centrifugal ultrafiltration with high-performance liquid chromatography-mass spectrometry (CU-LC-MS) was proposed. This method was used to analyze alpha-amylase inhibitors from Kadsura longipedunculata extract. According to previous screening with CU-LC-MS, two screened potential alpha-amylase inhibitors was successfully isolated from Kadsura longipedunculata extract using HSCCC under the optimized experimental conditions. The isolated two target compounds (with purities of 92.3% and 94.6%) were, respectively, identified as quercetin-3-O-rhamnoside (1) and protocatechuic acid (2) based on the MS, UV, and 1H-NMR spectrometry data. To verify the inhibition of screened compounds, the inhibitory activities of quercetin-3-O-rhamnoside (1) and protocatechuic acid (2) on alpha-amylase were tested, and it demonstrated that the experimental IC50 values of quercetin-3-O-rhamnoside (1) and protocatechuic acid (2) were 28.8 and 12.5 MUmol/L. These results proved that the hyphenated technique using CU-LC-MS and HSCCC was a rapid, competent, and reproductive method to screen and separate potential active compounds, like enzyme inhibitors from the extract of herbal medicines. PMID- 27617988 TI - Synthesis and Antimicrobial Evaluation of 1-[(2-Substituted phenyl)carbamoyl]naphthalen-2-yl Carbamates. AB - Series of thirteen 1-[(2-chlorophenyl)carbamoyl]naphthalen-2-yl carbamates and thirteen 1-[(2-nitrophenyl)carbamoyl]naphthalen-2-yl carbamates with alkyl/cycloalkyl/arylalkyl chains were prepared and characterized. Primary in vitro screening of the synthesized compounds was performed against Staphylococcus aureus, two methicillin-resistant S. aureus strains, Mycobacterium marinum, and M. kansasii. 1-[(2-Chlorophenyl)carbamoyl]naphthalen-2-yl ethylcarbamate and 1 [(2-nitrophenyl)carbamoyl]naphthalen-2-yl ethylcarbamate showed antistaphylococcal (MICs = 42 uM against MRSA) and antimycobacterial (MICs = 21 uM) activity against the tested strains comparable with or higher than that of the standards ampicillin and isoniazid. In the case of bulkier carbamate tails (R > propyl/isopropyl), the activity was similar (MICs ca. 70 uM). Screening of the cytotoxicity of both of the most effective compounds was performed using THP-1 cells, and no significant lethal effect was observed (LD50 >30 uM). The structure activity relationships are discussed. PMID- 27617990 TI - Chemical Composition, Antibacterial Properties and Mechanism of Action of Essential Oil from Clove Buds against Staphylococcus aureus. AB - The essential oil of clove has a wide range of pharmacological and biological activities and is widely used in the medicine, fragrance and flavoring industries. In this work, 22 components of the essential oil obtained from clove buds were identified. Eugenol was the major component (76.23%). The essential oil exhibited strong antibacterial activity against Staphylococcus aureus ATCC 25923 with a minimum inhibitory concentration (MIC) of 0.625 mg/mL, and the antibacterial effects depended on its concentration and action time. Kill-time assays also confirmed the essential oil had a significant effect on the growth rate of surviving S. aureus. We hypothesized that the essential oil may interact with the cell wall and membrane first. On the one hand it destroys cell wall and membranes, next causing the losses of vital intracellular materials, which finally result in the bacterial death. Besides, essential oil penetrates to the cytoplasmic membrane or enters inside the cell after destruction of cell structure, and then inhibits the normal synthesis of DNA and proteins that are required for bacterial growth. These results suggested that the effects of the clove essential oil on the growth inhibition of S. aureus may be at the molecular level rather than only physical damage. PMID- 27617989 TI - Comparison of Protein N-Homocysteinylation in Rat Plasma under Elevated Homocysteine Using a Specific Chemical Labeling Method. AB - Elevated blood concentrations of homocysteine have been well established as a risk factor for cardiovascular diseases and neuropsychiatric diseases, yet the etiologic relationship of homocysteine to these disorders remains poorly understood. Protein N-homocysteinylation has been hypothesized as a contributing factor; however, it has not been examined globally owing to the lack of suitable detection methods. We recently developed a selective chemical method to label N homocysteinylated proteins with a biotin-aldehyde tag followed by Western blotting analysis, which was further optimized in this study. We then investigated the variation of protein N-homocysteinylation in plasma from rats on a vitamin B12 deficient diet. Elevated "total homocysteine" concentrations were determined in rats with a vitamin B12 deficient diet. Correspondingly, overall levels of plasma protein N-homocysteinylation displayed an increased trend, and furthermore, more pronounced and statistically significant changes (e.g., 1.8 fold, p-value: 0.03) were observed for some individual protein bands. Our results suggest that, as expected, a general metabolic correlation exists between "total homocysteine" and N-homocysteinylation, although other factors are involved in homocysteine/homocysteine thiolactone metabolism, such as the transsulfuration of homocysteine by cystathionine beta-synthase or the hydrolysis of homocysteine thiolactone by paraoxonase 1 (PON1), may play more significant or direct roles in determining the level of N-homocysteinylation. PMID- 27617991 TI - Bioprinting and Differentiation of Stem Cells. AB - The 3D bioprinting of stem cells directly into scaffolds offers great potential for the development of regenerative therapies; in particular for the fabrication of organ and tissue substitutes. For this to be achieved; the lineage fate of bioprinted stem cell must be controllable. Bioprinting can be neutral; allowing culture conditions to trigger differentiation or alternatively; the technique can be designed to be stimulatory. Such factors as the particular bioprinting technique; bioink polymers; polymer cross-linking mechanism; bioink additives; and mechanical properties are considered. In addition; it is discussed that the stimulation of stem cell differentiation by bioprinting may lead to the remodeling and modification of the scaffold over time matching the concept of 4D bioprinting. The ability to tune bioprinting properties as an approach to fabricate stem cell bearing scaffolds and to also harness the benefits of the cells multipotency is of considerable relevance to the field of biomaterials and bioengineering. PMID- 27617992 TI - Characterization of French Coriander Oil as Source of Petroselinic Acid. AB - Coriander vegetable oil was extracted from fruits of French origin in a 23% yield. The oil was of good quality, with a low amount of free fatty acids (1.8%) and a concurrently high amount of triacylglycerols (98%). It is a rich source of petroselinic acid (C18:1n-12), an important renewable building block, making up 73% of all fatty acids, with also significant amounts of linoleic acid (14%), oleic acid (6%), and palmitic acid (3%). The oil was characterized by a high unsaponifiable fraction, comprising a substantial amount of phytosterols (6.70 g/kg). The main sterol markers were beta-sitosterol (35% of total sterols), stigmasterol (24%), and Delta7-stigmastenol (18%). Squalene was detected at an amount of 0.2 g/kg. A considerable amount of tocols were identified (500 mg/kg) and consisted mainly of tocotrienols, with gamma-tocotrienol as the major compound. The phospholipid content was low at 0.3%, of which the main phospholipid classes were phosphatidic acid (33%), phosphatidylcholine (25%), phosphatidylinositol (17%), and phosphatidylethanolamine (17%). About 50% of all phospholipids were non-hydratable. The beta-carotene content was low at 10 mg/kg, while a significant amount of chlorophyll was detected at about 11 mg/kg. An iron content of 1.4 mg/kg was determined through element analysis of the vegetable oil. The influence of fruit origin on the vegetable oil composition was shown to be very important, particularly in terms of the phospholipids, sterols, and tocols composition. PMID- 27617993 TI - Chemical and Antioxidant Properties of Wild Edible Mushrooms from Native Nothofagus spp. Forest, Argentina. AB - This study addresses issues regarding chemical and bioactive properties of nine wild edible mushrooms from native Nothofagus forest from Patagonia, Argentina. Macronutrients, sugars, fatty acids, tocopherols, organic acids, phenolic compounds and antioxidant properties were determined. Protein was found in high levels and varied between 3.35 g/100 g dw in Cyttaria hariotii and 22.29 g/100 g dw in Lepista nuda. All of them presented mannitol and trehalose as main sugars. Mannitol was significantly higher in Ramaria patagonica, although absent in Fistulina endoxantha, whereas trehalose predominated in Aleurodiscus vitellinus, Hydropus dusenii, Cortinarius magellanicus, C. hariotii, Grifola gargal and L. nuda, ranging from 1.15 to 10.26 g/100 g dw; it was absent in R. patagonica. The major fatty acid found was linoleic acid, followed by oleic acid and palmitic acid. All species presented oxalic and fumaric acids, while some also had malic, quinic and citric acids. Tocopherols composition was variable. Cortinarius magellanicus presented significantly higher contents of both alpha-tocopherol and beta-tocopherol. R. patagonica presented the best results in all the antioxidant activity assays (EC50 values <= 1 mg/mL) and the highest content of phenolic compounds presenting gallic, p-hydroxybenzoic, p-coumaric and cinnamic acids. This study constitutes the first report on chemical composition and nutritional value of most of these edible mushroom species. Furthermore, it provides important information necessary to characterize and define the use of these species as gastronomic delicacies, functional foods and sources of bioactive compounds. PMID- 27617994 TI - Synthesis and Anti-HIV-1 Activity Evaluation for Novel 3a,6a-Dihydro-1H pyrrolo[3,4-c]pyrazole-4,6-dione Derivatives. AB - The search for new molecular constructs that resemble the critical two-metal binding pharmacophore and the halo-substituted phenyl functionality required for HIV-1 integrase (IN) inhibition represents a vibrant area of research within drug discovery. As reported herein, we have modified our recently disclosed 1-[2-(4 fluorophenyl)ethyl]-pyrrole-2,5-dione scaffolds to design 35 novel compounds with improved biological activities against HIV-1. These new compounds show single digit micromolar antiviral potencies against HIV-1 and low toxicity. Among of them, compound 9g and 15i had potent anti-HIV-1 activities (EC50 < 5 MUM) and excellent therapeutic index (TI, CC50/EC50 > 100). These two compounds have potential as lead compounds for further optimization into clinical anti-HIV-1 agents. PMID- 27617995 TI - (+)-Podocarpic Acid as Chiral Template in the Synthesis of Aphidicolane, Stemodane and Stemarane Diterpenoids ?. AB - In this review the synthetic work in the field of aphidicolane, stemodane and stemarane diterpenoids, in which readily available (+)-podocarpic acid (4) was used as chiral template for the construction of their polycyclic structures, is described as it developed along the years. In the frame of this work (+) podocarpic acid (4) was a very useful tool in a model study leading to the syntheses of tetracyclic ketones 7 and 8, models of key intermediates 5a and 6 in the syntheses of (+)-aphidicolin (1) and (+)-stemodin (2a), respectively. (+) Podocarpic acid (4) was also converted into (+)-2-deoxystemodinone (2d), allowing confirmation of the stemodane diterpenoids absolute configuration, into (+) aphidicol-15-ene (36) and into Stemodia chilensis tetracyclic diterpenoid (+)-19 acetoxystemodan-12-ol (2f), allowing confirmation of its structure. (+) Podocarpic acid (4) was then extensively used in the work which led to the synthesis of (+)-stemar-13-ene (57) and (+)-18-deoxystemarin (3b). Finally, (+)-4 was converted into (+)-2-deoxyoryzalexin S (66), which made it possible to demonstrate that the structure of (+)-66 could not be attributed to a Chilean Calceolaria isolated diterpenoid to which this structure had been assigned. PMID- 27617996 TI - LC-MS Supported Studies on the in Vitro Metabolism of both Enantiomers of Flubatine and the in Vivo Metabolism of (+)-[(18)F]Flubatine-A Positron Emission Tomography Radioligand for Imaging alpha4beta2 Nicotinic Acetylcholine Receptors. AB - Both enantiomers of [(18)F]flubatine are promising radioligands for neuroimaging of alpha4beta2 nicotinic acetylcholine receptors (nAChRs) by positron emission tomography (PET). To support clinical studies in patients with early Alzheimer's disease, a detailed examination of the metabolism in vitro and in vivo has been performed. (+)- and (-)-flubatine, respectively, were incubated with liver microsomes from mouse and human in the presence of NADPH (beta-nicotinamide adenine dinucleotide 2'-phosphate reduced tetrasodium salt). Phase I in vitro metabolites were detected and their structures elucidated by LC-MS/MS (liquid chromatography-tandem mass spectrometry). Selected metabolite candidates were synthesized and investigated for structural confirmation. Besides a high level of in vitro stability, the microsomal incubations revealed some species differences as well as enantiomer discrimination with regard to the formation of monohydroxylated products, which was identified as the main metabolic pathway in this assay. Furthermore, after injection of 250 MBq (+)-[(18)F]flubatine (specific activity > 350 GBq/MUmol) into mouse, samples were prepared from brain, liver, plasma, and urine after 30 min and investigated by radio-HPLC (high performance liquid chromatography with radioactivity detection). For structure elucidation of the radiometabolites of (+)-[(18)F]flubatine formed in vivo, identical chromatographic conditions were applied to LC-MS/MS and radio-HPLC to compare samples obtained in vitro and in vivo. By this correlation approach, we assigned three of four main in vivo radiometabolites to products that are exclusively C- or N-hydroxylated at the azabicyclic ring system of the parent molecule. PMID- 27617997 TI - Synthesis and Cytotoxic Activity on Human Cancer Cells of Novel Isoquinolinequinone-Amino Acid Derivatives. AB - A variety of aminoisoquinoline-5,8-quinones bearing alpha-amino acids moieties were synthesized from 3-methyl-4-methoxycarbonylisoquinoline-5,8-quinone and diverse l- and d-alpha-amino acid methyl esters. The members of the series were evaluated for their cytotoxic activity against normal and cancer cell lines by using the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay. From the current investigation, structure-activity relationships demonstrate that the location and structure of the amino acid fragment plays a significant role in the cytotoxic effects. Moderate to high cytotoxic activity was observed and four members, derived from l-alanine, l-leucine, l phenylalanine, and d-phenylalanine, were selected as promising compounds by their IC50 ranging from 0.5 to 6.25 MUM and also by their good selectivity indexes (>=2.24). PMID- 27617998 TI - NO-Releasing Enmein-Type Diterpenoid Derivatives with Selective Antiproliferative Activity and Effects on Apoptosis-Related Proteins. AB - A series of nine enmein-type ent-kaurane diterpenoid and furoxan-based nitric oxide (NO) donor hybrids (10a-i) were designed and synthesized from commercially available oridonin (1). These hybrids were evaluated for their antiproliferative activity against Bel-7402, K562, MGC-803, and CaEs-17 human cancer cell lines and L-02 normal liver cells. The antiproliferative activity against tumor cells was stronger than the lead compound 1 and parent molecule 9 in most cases. Especially, compound 10f showed the strongest activity against human hepatocarcinoma Bel-7402 cell line with an IC50 of 0.81 MUM and could also release 33.7 MUmol/L NO at the time point of 60 min. Compounds 10a-i also showed cytotoxic selectivity between tumor and normal liver cells with IC50 ranging from 22.1 to 33.9 MUM. Furthermore, the apoptotic properties on Bel-7402 cells revealed that 10f could induce S phase cell cycle arrest and apoptosis at low micromolar concentrations. The effects of 10f on apoptosis-related proteins were also investigated. The potent antiproliferative activities and mechanistic studies warrant further preclinical investigations. PMID- 27617999 TI - A Highly Efficient and Reusable Palladium(II)/Cationic 2,2'-Bipyridyl-Catalyzed Stille Coupling in Water. AB - A water-soluble PdCl2(NH3)2/cationic 2,2'-bipyridyl system was found to be a highly efficient catalyst for Stille coupling of aryl iodides and bromides with organostannanes. The coupling reaction was conducted at 110 degrees C in water, under aerobic conditions, in the presence of NaHCO3 as a base to afford corresponding Stille coupling products in good to high yields. When aryltributylstannanes were employed, the reactions proceeded smoothly under a very low catalyst loading (as little as 0.0001 mol %). After simple extraction, the residual aqueous phase could be reused in subsequent runs, making this Stille coupling economical. In the case of tetramethylstannane, however, a greater catalyst loading (1 mol %) and the use of tetraethylammonium iodide as a phase transfer agent were required in order to obtain satisfactory yields. PMID- 27618000 TI - Improvement in Flavonoids and Phenolic Acids Production and Pharmaceutical Quality of Sweet Basil (Ocimum basilicum L.) by Ultraviolet-B Irradiation. AB - Sweet basil (Ocimum basilicum Linnaeus) is aromatic herb that has been utilized in traditional medicine. To improve the phytochemical constituents and pharmaceutical quality of sweet basil leaves, ultraviolet (UV)-B irradiation at different intensities (2.30, 3.60, and 4.80 W/m2) and durations (4, 6, 8, and 10 h) was applied at the post-harvest stage. Total flavonoid content (TFC) and total phenolic content (TPC) were measured using spectrophotometric method, and individual flavonoids and phenolic acids were identified using ultra-high performance liquid chromatography. As a key enzyme for the metabolism of flavonoids, chalcone synthase (CHS) activity, was measured using a CHS assay. Antioxidant activity and antiproliferative activity of extracts against a breast cancer cell line (MCF-7) were evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH) assays and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays, respectively. UV-B irradiation at an intensity of 3.60 W/m2 increased TFC approximately 0.85-fold and also increased quercetin (0.41-fold), catechin (0.85-fold), kaempferol (0.65-fold) rutin (0.68-fold) and luteolin (1.00 fold) content. The highest TPC and individual phenolic acid (gallic acid, cinnamic acid and ferulic acid) was observed in the 3.60 W/m2 of UV-B treatment. Cinnamic acid and luteolin were not detected in the control plants, production being induced by UV-B irradiation. Production of these secondary metabolites was also significantly influenced by the duration of UV-B irradiation. Irradiation for 8-h led to higher TFC, TPC and individual flavonoids and phenolic acids than for the other durations (4, 8, and 10-h) except for cinnamic acid, which was detected at higher concentration when irradiated for 6-h. Irradiation for 10-h significantly decreased the secondary metabolite production in sweet basil leaves. CHS activity was induced by UV-B irradiation and highest activity was observed at 3.60 W/m2 of UV-B irradiation. UV-B treated leaves presented the highest DPPH activity and antiproliferative activity with a half-maximal inhibitory concentration (IC50) value of 56.0 and 40.8 ug/mL, respectively, over that of the control plants (78.0 and 58.2 ug/mL, respectively). These observations suggest that post-harvest irradiation with UV-B can be considered a promising technique to improve the healthy-nutritional and pharmaceutical properties of sweet basil leaves. PMID- 27618001 TI - Effects of Culture Substrate Made of Poly(N-isopropylacrylamide-co-acrylic acid) Microgels on Osteogenic Differentiation of Mesenchymal Stem Cells. AB - Poly(N-isopropylacrylamide) (PNIPAM)-based polymers and gels are widely known and studied for their thermoresponsive property. In the biomaterials category, they are regarded as a potential cell culture substrate, not only because of their biocompatibility, but also their special character of allowing controlled detachment of cells via temperature stimulus. Previous research about PNIPAM based substrates mostly concentrated on their effects in cell adhesion and proliferation. In this study, however, we investigate the influence of the PNIPAM based substrate on the differentiation capacity of stem cells. Especially, we choose P(NIPAM-AA) microgels as a culture dish coating and mesenchymal stem cells (MSCs) are cultured on top of the microgels. Interestingly, we find that the morphology of MSCs changes remarkably on a microgel-coated surface, from the original spindle form to a more stretched and elongated cell shape. Accompanied by the alternation in morphology, the expression of several osteogenesis-related genes is elevated even without inducing factors. In the presence of full osteogenic medium, MSCs on a microgel substrate show an enhancement in the expression level of osteopontin and alizarin red staining signals, indicating the physical property of substrate has a direct effect on MSCs differentiation. PMID- 27618002 TI - Immobilization of alpha-Amylase from Anoxybacillus sp. SK3-4 on ReliZyme and Immobead Supports. AB - alpha-Amylase from Anoxybacillus sp. SK3-4 (ASKA) is a thermostable enzyme that produces a high level of maltose from starches. A truncated ASKA (TASKA) variant with improved expression and purification efficiency was characterized in an earlier study. In this work, TASKA was purified and immobilized through covalent attachment on three epoxide (ReliZyme EP403/M, Immobead IB-150P, and Immobead IB 150A) and an amino-epoxide (ReliZyme HFA403/M) activated supports. Several parameters affecting immobilization were analyzed, including the pH, temperature, and quantity (mg) of enzyme added per gram of support. The influence of the carrier surface properties, pore sizes, and lengths of spacer arms (functional groups) on biocatalyst performances were studied. Free and immobilized TASKAs were stable at pH 6.0-9.0 and active at pH 8.0. The enzyme showed optimal activity and considerable stability at 60 degrees C. Immobilized TASKA retained 50% of its initial activity after 5-12 cycles of reuse. Upon degradation of starches and amylose, only immobilized TASKA on ReliZyme HFA403/M has comparable hydrolytic ability with the free enzyme. To the best of our knowledge, this is the first report of an immobilization study of an alpha-amylase from Anoxybacillus spp. and the first report of alpha-amylase immobilization using ReliZyme and Immobeads as supports. PMID- 27618003 TI - Synthesis and Antimicrobial Characterization of Half-Calycanthaceous Alkaloid Derivatives. AB - A total of 29 novel tetrahydropyrroloindol-based calycanthaceous alkaloid derivatives were synthesized from indole-3-acetonitrile in good yields. The synthesized compounds were evaluated against nine strains of bacteria and a wide range of plant pathogen fungi. Bioassay results revealed that majority of the compounds displayed similar or higher in vitro antimicrobial activities than the positive control. The biological activities also indicated that substituents at R4 and R5 significantly affect the activities. Notably, compound c4 was found to be most active among the tested calycanthaceous analogues and might be a novel potential leading compound for further development as an antifungal agent. The results could pave the way for further design and structural modification of calycanthaceous alkaloids as antimicrobial agents. PMID- 27618004 TI - Chemical Analysis of Dietary Constituents in Rosa roxburghii and Rosa sterilis Fruits. AB - Both Rosa roxburghii and R. sterilis, belonging to the Rosaceae, are endemic species in Guizhou Province, China. The fruits of these two species are mixed used as functional food in the region. Aiming to elucidate the phytochemical characteristics of R. roxburghii and R. sterilis fruits, the essential oils and constituents in a methanol extract have been analyzed and compared by GC-MS and UFLC/Q-TOF-MS, respectively. As a result, a total of 135 volatile compounds were identified by GC-MS and 91 components were different between R. roxburghii and R. sterilis fruits; a total of 59 compounds in methanol extracts were identified by UFLC/Q-TOF-MS, including 13 organic acids, 12 flavonoids, 11 triterpenes, nine amino acids, five phenylpropanoid derivatives, four condensed tannins, two stilbenes, two benzaldehyde derivatives and one benzoic acid derivative; and nine characteristic compounds were found between R. roxburghii and R. sterilis fruits. This systematic study plays an important role for R. roxburghii and R. sterilis fruits in the product development. PMID- 27618005 TI - Anti-Inflammatory Effects and Mechanisms of Action of Coussaric and Betulinic Acids Isolated from Diospyros kaki in Lipopolysaccharide-Stimulated RAW 264.7 Macrophages. AB - Diospyros kaki Thunb. is widely distributed in East Asian countries, its leaves being mainly used for making tea. In this study, coussaric acid (CA) and betulinic acid (BA), both triterpenoid compounds, were obtained from D. kaki leaf extracts through bioassay-guided isolation. CA and BA showed anti-inflammatory effects via inhibition of the nuclear factor-kappaB (NF-kappaB) pathway, providing important information on their anti-inflammatory mechanism. Furthermore, they markedly inhibited nitric oxide (NO) and prostaglandin E2 (PGE2) production in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages, and suppressed tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1beta (IL-1beta) levels. Furthermore, they decreased protein expression of inducible nitric oxide synthase and cyclooxygenase-2. Pre-treatment with CA and BA inhibited LPS-induced NF-kappaB. We further examined the effects of CA and BA on heme oxygenase (HO)-1 expression in RAW 264.7 macrophages: BA induced HO-1 protein expression in a dose-dependent manner, while CA had no effect. We also investigated whether BA treatment induced nuclear translocation of Nrf2. BA inhibited LPS-induced NF-kappaB-binding activity, as well as pro inflammatory mediator and cytokine production (e.g., NO, PGE2, TNF-alpha, IL 1beta, IL-6), by partial reversal of this effect by SnPP, an inhibitor of HO-1. These findings further elucidate the anti-inflammatory mechanism of CA and BA isolated from D. kaki. PMID- 27618006 TI - Impact of Biohybrid Magnetite Nanoparticles and Moroccan Propolis on Adherence of Methicillin Resistant Strains of Staphylococcus aureus. AB - Biofilm bacteria are more resistant to antibiotics than planktonic cells. Propolis possesses antimicrobial activity. Generally, nanoparticles containing heavy metals possess antimicrobial and antibiofilm properties. In this study, the ability of adherence of Methicillin Resistant Strains of Staphylococcus aureus (MRSA) to catheters treated with magnetite nanoparticles (MNPs), produced by three methods and functionalized with oleic acid and a hydro-alcoholic extract of propolis from Morocco, was evaluated. The chemical composition of propolis was established by gas chromatography mass spectrometry (GC-MS), and the fabricated nanostructures characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), Mossbauer spectroscopy and Fourrier transform infrared spectroscopy (FTIR). The capacity for impairing biofilm formation was dependent on the strain, as well as on the mode of production of MNPs. The co-precipitation method of MNPs fabrication using Fe(3+) and Na2SO3 solution and functionalized with oleic acid and propolis was the most effective in the impairment of adherence of all MRSA strains to catheters (p < 0.001). The adherence of the strain MRSA16 was also significantly lower (p < 0.001) when the catheters were treated with the hybrid MNPs with oleic acid produced by a hydrothermal method. The anti-MRSA observed can be attributed to the presence of benzyl caffeate, pinocembrin, galangin, and isocupressic acid in propolis extract, along with MNPs. However, for MRSA16, the impairment of its adherence on catheters may only be attributed to the hybrid MNPs with oleic acid, since very small amount, if any at all of propolis compounds were added to the MNPs. PMID- 27618007 TI - BL-038, a Benzofuran Derivative, Induces Cell Apoptosis in Human Chondrosarcoma Cells through Reactive Oxygen Species/Mitochondrial Dysfunction and the Caspases Dependent Pathway. AB - Chondrosarcoma is a highly malignant cartilage-forming bone tumor that has the capacity to invade locally and cause distant metastasis. Moreover, chondrosarcoma is intrinsically resistant to conventional chemotherapy or radiotherapy. The novel benzofuran derivative, BL-038 (2-amino-3-(2,6-dichlorophenyl)-6-(4 methoxyphenyl)benzofuran-4-yl acetate), has been evaluated for its anticancer effects in human chondrosarcoma cells. BL-038 caused cell apoptosis in two human chondrosarcoma cell lines, JJ012 and SW1353, but not in primary chondrocytes. Treatment of chondrosarcoma with BL-038 also induced reactive oxygen species (ROS) production. Furthermore, BL-038 decreased mitochondrial membrane potential (MMP) and changed mitochondrial-related apoptosis, by downregulating the anti apoptotic activity members (Bcl-2, Bcl-xL) and upregulating pro-apoptotic members (Bax, Bak) of the B-cell lymphoma 2 (Bcl-2) family of proteins, key regulators of the apoptotic machinery in cells. These results demonstrate that in human chondrosarcoma cells, the apoptotic and cytotoxic effects of BL-038 are mediated by the intrinsic mitochondria-mediated apoptotic pathway, which in turn causes the release of cytochrome c, the activation of caspase-9 and caspase-3, and the cleavage of poly (ADP-ribose) polymerase (PARP), to elicit apoptosis response. Our results show that the benzofuran derivative BL-038 induces apoptosis in chondrosarcoma cells. PMID- 27618009 TI - Subchondral Bone Plate Changes More Rapidly than Trabecular Bone in Osteoarthritis. AB - Osteoarthritis (OA) is the most common joint disorder, characterised by focal loss of cartilage and increased subchondral bone remodelling at early OA stages of the disease. We have investigated the temporal and the spatial relationship between bone remodelling in subchondral bone plate (Sbp) and trabecular bone (Tb) in Dunkin Hartley (DH, develop OA early) and the Bristol Strain 2 (BS2, control which develop OA late) guinea pigs. Right tibias were dissected from six male animals of each strain, at 10, 16, 24 and 30 weeks of age. Micro-computed tomography was used to quantify the growth plate thickness (GpTh), subchondral bone plate thickness (SbpTh) and trabecular bone thickness (TbTh), and bone mineral density (BMD) in both Sbp and Tb. The rate of change was calculated for 10-16 weeks, 16-24 weeks and 24-30 weeks. The rate of changes in Sbp and Tb thickness at the earliest time interval (10-16 weeks) were significantly greater in DH guinea pigs than in the growth-matched control strain (BS2). The magnitude of these differences was greater in the medial side than the lateral side (DH: 22.7 and 14.75 um/week, BS2: 5.63 and 6.67 um/week, respectively). Similarly, changes in the BMD at the earliest time interval was greater in the DH strain than the BS2, again more pronounced in the disease prone medial compartment (DH: 0.0698 and 0.0372 g/cm3/week, BS2: 0.00457 and 0.00772 g/cm3/week, respectively). These changes observed preceded microscopic and cellular signs of disease as previously reported. The rapid early changes in SbpTh, TbTh, Sbp BMD and Tb BMD in the disease prone DH guinea pigs compared with the BS2 control strain suggest a link to early OA pathology. This is corroborated by the greater relative changes in subchondral bone in the medial compared with the lateral compartment. PMID- 27618008 TI - Physiological and Pathogenic Roles of Prolyl Isomerase Pin1 in Metabolic Regulations via Multiple Signal Transduction Pathway Modulations. AB - Prolyl isomerases are divided into three groups, the FKBP family, Cyclophilin and the Parvulin family (Pin1 and Par14). Among these isomerases, Pin1 is a unique prolyl isomerase binding to the motif including pSer/pThr-Pro that is phosphorylated by kinases. Once bound, Pin1 modulates the enzymatic activity, protein stability or subcellular localization of target proteins by changing the cis- and trans-formations of proline. Several studies have examined the roles of Pin1 in the pathogenesis of cancers and Alzheimer's disease. On the other hand, recent studies have newly demonstrated Pin1 to be involved in regulating glucose and lipid metabolism. Interestingly, while Pin1 expression is markedly increased by high-fat diet feeding, Pin1 KO mice are resistant to diet-induced obesity, non alcoholic steatohepatitis and diabetic vascular dysfunction. These phenomena result from the binding of Pin1 to several key factors regulating metabolic functions, which include insulin receptor substrate-1, AMPK, Crtc2 and NF-kappaB p65. In this review, we focus on recent advances in elucidating the physiological roles of Pin1 as well as the pathogenesis of disorders involving this isomerase, from the viewpoint of the relationships between signal transductions and metabolic functions. PMID- 27618010 TI - Advances and Future Applications of Augmented Peripheral Nerve Regeneration. AB - Peripheral nerve injuries remain a significant source of long lasting morbidity, disability, and economic costs. Much research continues to be performed in areas related to improving the surgical outcomes of peripheral nerve repair. In this review, the physiology of peripheral nerve regeneration and the multitude of efforts to improve surgical outcomes are discussed. Improvements in tissue engineering that have allowed for the use of synthetic conduits seeded with neurotrophic factors are highlighted. Selected pre-clinical and available clinical data using cell based methods such as Schwann cell, undifferentiated, and differentiated stem cell transplantation to guide and enhance peripheral nerve regeneration are presented. The limitations that still exist in the utility of neurotrophic factors and cell-based therapies are outlined. Strategies that are most promising for translation into the clinical arena are suggested. PMID- 27618011 TI - Comparative Study of Ultrasonication-Induced and Naturally Self-Assembled Silk Fibroin-Wool Keratin Hydrogel Biomaterials. AB - This study reports the formation of biocompatible hydrogels using protein polymers from natural silk cocoon fibroins and sheep wool keratins. Silk fibroin protein contains beta-sheet secondary structures, allowing for the formation of physical cross-linkers in the hydrogels. Comparative studies were performed on two groups of samples. In the first group, ultrasonication was used to induce a quick gelation of a protein aqueous solution, enhancing the ability of Bombyx mori silk fibroin chains to quickly entrap the wool keratin protein molecules homogenously. In the second group, silk/keratin mixtures were left at room temperature for days, resulting in naturally-assembled gelled solutions. It was found that silk/wool blended solutions can form hydrogels at different mixing ratios, with perfectly interconnected gel structure when the wool content was less than 30 weight percent (wt %) for the first group (ultrasonication), and 10 wt % for the second group (natural gel). Differential scanning calorimetry (DSC) and temperature modulated DSC (TMDSC) were used to confirm that the fibroin/keratin hydrogel system was well-blended without phase separation. Fourier transform infrared spectroscopy (FTIR) was used to investigate the secondary structures of blended protein gels. It was found that intermolecular beta-sheet contents significantly increase as the system contains more silk for both groups of samples, resulting in stable crystalline cross-linkers in the blended hydrogel structures. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) were used to analyze the samples' characteristic morphology on both micro- and nanoscales, which showed that ultrasonic waves can significantly enhance the cross-linker formation and avoid phase separation between silk and keratin molecules in the blended systems. With the ability to form cross-linkages non-chemically, these silk/wool hydrogels may be economically useful for various biomedical applications, thanks to the good biocompatibility of protein molecules and the various characteristics of hydrogel systems. PMID- 27618012 TI - Identifying Virulence-Associated Genes Using Transcriptomic and Proteomic Association Analyses of the Plant Parasitic Nematode Bursaphelenchus mucronatus. AB - Bursaphelenchus mucronatus (B. mucronatus) isolates that originate from different regions may vary in their virulence, but their virulence-associated genes and proteins are poorly understood. Thus, we conducted an integrated study coupling RNA-Seq and isobaric tags for relative and absolute quantitation (iTRAQ) to analyse transcriptomic and proteomic data of highly and weakly virulent B. mucronatus isolates during the pathogenic processes. Approximately 40,000 annotated unigenes and 5000 proteins were gained from the isolates. When we matched all of the proteins with their detected transcripts, a low correlation coefficient of r = 0.138 was found, indicating probable post-transcriptional gene regulation involved in the pathogenic processes. A functional analysis showed that five differentially expressed proteins which were all highly expressed in the highly virulent isolate were involved in the pathogenic processes of nematodes. Peroxiredoxin, fatty acid- and retinol-binding protein, and glutathione peroxidase relate to resistance against plant defence responses, while beta-1,4-endoglucanase and expansin are associated with the breakdown of plant cell walls. Thus, the pathogenesis of B. mucronatus depends on its successful survival in host plants. Our work adds to the understanding of B. mucronatus' pathogenesis, and will aid in controlling B. mucronatus and other pinewood nematode species complexes in the future. PMID- 27618013 TI - Synthesis and Characterization of Some New Bis-Pyrazolyl-Thiazoles Incorporating the Thiophene Moiety as Potent Anti-Tumor Agents. AB - A new series of 1,4-bis(1-(5-(aryldiazenyl)thiazol-2-yl)-5-(thiophen-2-yl)-4,5 dihydro-1H-pyrazol-3-yl)benzenes 3a-i were synthesized via reaction of 5,5'-(1,4 phenylene)bis(3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamide) (1) with hydrazonoyl halides 2a-i. In addition, reaction of 1 with ethyl chloroacetate afforded bis-thiazolone derivative 8 as the end product. Reaction of compound 8 with methyl glyoxalate gave bis-thiazolone derivative 10. The structures of the newly synthesized compounds were established on the basis of spectroscopic evidences and their alternative syntheses. All the synthesized compounds were evaluated for their anti-tumor activities against hepatocellular carcinoma (HepG2) cell lines, and the results revealed promising activities of compounds 3g, 5e, 3e, 10, 5f, 3i, and 3f with IC50 equal 1.37 +/- 0.15, 1.41 +/- 0.17, 1.62 +/- 0.20, 1.86 +/- 0.20, 1.93 +/- 0.08, 2.03 +/- 0.25, and 2.09 +/- 0.19 MUM, respectively. PMID- 27618015 TI - Six2 Is a Coordinator of LiCl-Induced Cell Proliferation and Apoptosis. AB - The metanephric mesenchyme (MM) cells are a subset of kidney progenitor cells and play an essential role in mesenchymal-epithelial transition (MET), the key step of nephron generation. Six2, a biological marker related to Wnt signaling pathway, promotes the proliferation, inhibits the apoptosis and maintains the un differentiation of MM cells. Besides, LiCl is an activator of Wnt signaling pathway. However, the role of LiCl in cellular regulation of MM cells remains unclear, and the relationship between LiCl and Six2 in this process is also little known. Here, we performed EdU assay and flow cytometry assay to, respectively, detect the proliferation and apoptosis of MM cells treated with LiCl of increasing dosages. In addition, reverse transcription-PCR (RT-PCR) and Western-blot were conducted to measure the expression of Six2 and some maker genes of Wnt and bone-morphogenetic-protein (BMP) signaling pathway. Furthermore, luciferase assay was also carried out to detect the transcriptional regulation of Six2. Then we found LiCl promoted MM cell proliferation at low-concentration (10, 20, 30, and 40 mM). The expression of Six2 was dose-dependently increased in low concentration (10, 20, 30, and 40 mM) at both mRNA and protein level. In addition, both of cell proliferation and Six2 expression in MM cells declined when dosage reached high-concentration (50 mM). However, Six2 knock-down converted the proliferation reduction at 50 mM. Furthermore, Six2 deficiency increased the apoptosis of MM cells, compared with negative control cells at relative LiCl concentration. However, the abnormal rise of apoptosis at 30 mM of LiCl concentration implies that it might be the reduction of GSK3beta that increased cell apoptosis. Together, these demonstrate that LiCl can induce the proliferation and apoptosis of MM cells coordinating with Six2. PMID- 27618018 TI - Property Characterization and Photocatalytic Activity Evaluation of BiGdO3 Nanoparticles under Visible Light Irradiation. AB - BiGdO3 nanoparticles were prepared by a solid-state reaction method and applied in photocatalytic degradation of dyes in this study. BiGdO3 was characterized by X-ray powder diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy, Brunauer-Emmett-Teller, UV-Vis diffuse reflectance spectroscopy and transmission electron microscopy. The results showed that BiGdO3 crystallized well with the fluorite-type structure, a face-centered cubic crystal system and a space group Fm3m 225. The lattice parameter of BiGdO3 was 5.465 angstrom. The band gap of BiGdO3 was estimated to be 2.25 eV. BiGdO3 showed a strong optical absorption during the visible light region. Moreover, the photocatalytic activity of BiGdO3 was evaluated by photocatalytic degradation of direct dyes in aqueous solution under visible light irradiation. BiGdO3 demonstrated excellent photocatalytic activity in degrading Direct Orange 26 (DO-26) or Direct Red 23 (DR-23) under visible light irradiation. The photocatalytic degradation of DO-26 or DR-23 followed the first-order reaction kinetics, and the first-order rate constant was 0.0046 or 0.0023 min(-1) with BiGdO3 as catalyst. The degradation intermediates of DO-26 were observed and the possible photocatalytic degradation pathway of DO-26 under visible light irradiation was provided. The effect of various operational parameters on the photocatalytic activity and the stability of BiGdO3 particles were also discussed in detail. BiGdO3/(visible light) photocatalysis system was confirmed to be suitable for textile industry wastewater treatment. PMID- 27618014 TI - Moving Past Anti-VEGF: Novel Therapies for Treating Diabetic Retinopathy. AB - Diabetic retinopathy is the leading cause of blindness in working age adults, and is projected to be a significant future health concern due to the rising incidence of diabetes. The recent advent of anti-vascular endothelial growth factor (VEGF) antibodies has revolutionized the treatment of diabetic retinopathy but a significant subset of patients fail to respond to treatment. Accumulating evidence indicates that inflammatory cytokines and chemokines other than VEGF may contribute to the disease process. The current review examines the presence of non-VEGF cytokines in the eyes of patients with diabetic retinopathy and highlights mechanistic pathways in relevant animal models. Finally, novel drug targets including components of the kinin-kallikrein system and emerging treatments such as anti-HPTP (human protein tyrosine phosphatase) beta antibodies are discussed. Recognition of non-VEGF contributions to disease pathogenesis may lead to novel therapeutics to enhance existing treatments for patients who do not respond to anti-VEGF therapies. PMID- 27618016 TI - Ion Channels in Brain Metastasis. AB - Breast cancer, lung cancer and melanoma exhibit a high metastatic tropism to the brain. Development of brain metastases severely worsens the prognosis of cancer patients and constrains curative treatment options. Metastasizing to the brain by cancer cells can be dissected in consecutive processes including epithelial mesenchymal transition, evasion from the primary tumor, intravasation and circulation in the blood, extravasation across the blood-brain barrier, formation of metastatic niches, and colonization in the brain. Ion channels have been demonstrated to be aberrantly expressed in tumor cells where they regulate neoplastic transformation, malignant progression or therapy resistance. Moreover, many ion channel modulators are FDA-approved drugs and in clinical use proposing ion channels as druggable targets for future anti-cancer therapy. The present review article aims to summarize the current knowledge on the function of ion channels in the different processes of brain metastasis. The data suggest that certain channel types involving voltage-gated sodium channels, ATP-release channels, ionotropic neurotransmitter receptors and gap junction-generating connexins interfere with distinct processes of brain metastazation. PMID- 27618017 TI - Analysis of Large Seeds from Three Different Medicago truncatula Ecotypes Reveals a Potential Role of Hormonal Balance in Final Size Determination of Legume Grains. AB - Legume seeds are important as protein and oil source for human diet. Understanding how their final seed size is determined is crucial to improve crop yield. In this study, we analyzed seed development of three accessions of the model legume, Medicago truncatula, displaying contrasted seed size. By comparing two large seed accessions to the reference accession A17, we described mechanisms associated with large seed size determination and potential factors modulating the final seed size. We observed that early events during embryogenesis had a major impact on final seed size and a delayed heart stage embryo development resulted to large seeds. We also observed that the difference in seed growth rate was mainly due to a difference in embryo cell number, implicating a role of cell division rate. Large seed accessions could be explained by an extended period of cell division due to a longer embryogenesis phase. According to our observations and recent reports, we observed that auxin (IAA) and abscisic acid (ABA) ratio could be a key determinant of cell division regulation at the end of embryogenesis. Overall, our study highlights that timing of events occurring during early seed development play decisive role for final seed size determination. PMID- 27618019 TI - Biased and Unbiased Methods for the Detection of Off-Target Cleavage by CRISPR/Cas9: An Overview. AB - The clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 endonuclease (Cas9) derived from bacterial adaptive immune systems is a revolutionary tool used in both basic and applied science. It is a versatile system that enables the genome of different species to be modified by generating double strand breaks (DSBs) at specific locations. However, all of the CRISPR/Cas9 systems can also produce DSBs at off-target sites that differ substantially from on-target sites. The generation of DSBs in locations outside the intended site can produce mutations that need to be carefully monitored, especially when using these tools for therapeutic purposes. However, off-target analyses of the CRISPR/Cas9 system have been very challenging, particularly when performed directly in cells. In this manuscript, we review the different strategies developed to identify off-targets generated by CRISPR/cas9 systems and other specific nucleases (ZFNs, TALENs) in real target cells. PMID- 27618020 TI - Downregulation of FOXP1 Inhibits Cell Proliferation in Hepatocellular Carcinoma by Inducing G1/S Phase Cell Cycle Arrest. AB - Forkhead box P1 (FOXP1) belongs to a family of winged-helix transcription factors that are involved in the processes of cellular proliferation, differentiation, metabolism, and longevity. FOXP1 can affect cell proliferation and migratory ability in hepatocellular carcinoma (HCC) in vitro. However, little is known about the mechanism of FOXP1 in the proliferation of HCC cells. This study aimed to further explore the function of FOXP1 on the proliferation of HCC cells as well as the relevant mechanism involved. Western blot analysis, tumor xenograft models, and flow cytometry analysis were performed to elucidate the function of FOXP1 in the regulation of cell proliferation in human HCC. We observed that silencing FOXP1 significantly suppressed the growth ability of HCC cells both in vitro and in vivo. In addition, knockdown of FOXP1 induced G1/S phase arrest, and the expression of total and phosphorylated Rb (active type) as well as the levels of E2F1 were markedly decreased at 24 h; however, other proteins, including cyclin-dependent kinase (CDK) 4 and 6 and cyclin D1 did not show noticeable changes. In conclusion, downregulation of FOXP1 inhibits cell proliferation in hepatocellular carcinoma by inducing G1/S phase cell cycle arrest, and the decrease in phosphorylated Rb is the main contributor to this G1/S phase arrest. PMID- 27618022 TI - Experimental Dissection of Metalloproteinase Inhibition-Mediated and Toxic Effects of Phenanthroline on Zebrafish Development. AB - Metalloproteinases are zinc-dependent endopeptidases that function as primary effectors of tissue remodeling, cell-signaling, and many other roles. Their regulation is ferociously complex, and is exquisitely sensitive to their molecular milieu, making in vivo studies challenging. Phenanthroline (PhN) is an inexpensive, broad-spectrum inhibitor of metalloproteinases that functions by chelating the catalytic zinc ion, however its use in vivo has been limited due to suspected off-target effects. PhN is very similar in structure to phenanthrene (PhE), a well-studied poly aromatic hydrocarbon (PAH) known to cause toxicity in aquatic animals by activating the aryl hydrocarbon receptor (AhR). We show that zebrafish are more sensitive to PhN than PhE, and that PhN causes a superset of the effects caused by PhE. Morpholino knock-down of the AhR rescues the effects of PhN that are shared with PhE, suggesting these are due to PAH toxicity. The effects of PhN that are not shared with PhE (specifically disruption of neural crest development and angiogenesis) involve processes known to depend on metalloproteinase activity. Furthermore these PhN-specific effects are not rescued by AhR knock-down, suggesting that these are bona fide effects of metalloproteinase inhibition, and that PhN can be used as a broad spectrum metalloproteinase inhibitor for studies with zebrafish in vivo. PMID- 27618023 TI - Circulating Tumor Cells (CTC) and Cell-Free DNA (cfDNA) Workshop 2016: Scientific Opportunities and Logistics for Cancer Clinical Trial Incorporation. AB - Despite the identification of circulating tumor cells (CTCs) and cell-free DNA (cfDNA) as potential blood-based biomarkers capable of providing prognostic and predictive information in cancer, they have not been incorporated into routine clinical practice. This resistance is due in part to technological limitations hampering CTC and cfDNA analysis, as well as a limited understanding of precisely how to interpret emergent biomarkers across various disease stages and tumor types. In recognition of these challenges, a group of researchers and clinicians focused on blood-based biomarker development met at the Canadian Cancer Trials Group (CCTG) Spring Meeting in Toronto, Canada on 29 April 2016 for a workshop discussing novel CTC/cfDNA technologies, interpretation of data obtained from CTCs versus cfDNA, challenges regarding disease evolution and heterogeneity, and logistical considerations for incorporation of CTCs/cfDNA into clinical trials, and ultimately into routine clinical use. The objectives of this workshop included discussion of the current barriers to clinical implementation and recent progress made in the field, as well as fueling meaningful collaborations and partnerships between researchers and clinicians. We anticipate that the considerations highlighted at this workshop will lead to advances in both basic and translational research and will ultimately impact patient management strategies and patient outcomes. PMID- 27618024 TI - Increased Serum Levels of Anti-Carbamylated 78-kDa Glucose-Regulated Protein Antibody in Patients with Rheumatoid Arthritis. AB - The objective of this study was to investigate the presence and titer of anti carbamylated 78-kDa glucose-regulated protein (anti-CarGRP78) antibody in serum from controls, and patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and primary Sjogren syndrome (pSS). Thirty-three RA patients, 20 SLE patients, 20 pSS patients, and 20 controls were enrolled from our outpatient clinic. GRP78 was cloned and carbamylated. Serum titers of anti- cyclic citrullinated peptides (anti-CCP), anti-GRP78, and anti-CarGRP78 were measured with an enzyme-linked immunosorbent assay. No differences in serum titers of anti-GRP78 antibody in patients with RA, SLE, or pSS compared with the controls were observed. Serum levels of anti-carGRP78 antibody in patients with RA, but not SLE or pSS, were significantly higher compared with the controls (OD405 0.15 +/- 0.08 versus 0.11 +/- 0.03, p = 0.033). There was a positive correlation between the serum levels of anti-GRP78 antibody, but not anti CarGRP78 antibody, with the levels of anti-CCP antibody in patients with RA. Both anti-GRP78 and anti-carGRP78 antibodies failed to correlate with C-reactive protein levels in patients with RA. In conclusion, we demonstrated the presence of anti-CarGRP78 antibody in patients with RA. In addition, the serum titer of anti-CarGRP78 antibody was significantly elevated in patients with RA compared with the controls. Anti-CarGRP78 antibody could also be detected in patients with SLE or pSS. PMID- 27618025 TI - Secondary Metabolites of the Endophytic Fungus Lachnum abnorme from Ardisia cornudentata. AB - Fractionation of an EtOAc-soluble fraction of the solid fermentate of an endophytic fungus, Lachnum abnorme Mont. BCRC 09F0006, derived from the endemic plant, Ardisia cornudentata Mez. (Myrsinaceae), resulted in the isolation of three new chromones, lachnochromonins D-F (1-3), one novel compound, lachabnormic acid (4), along with nine known compounds (5-13). Their structures were elucidated by spectroscopic analyses. Alternariol-3,9-dimethyl ether (6) was given the correct data as well as 2D spectral analyses for the first time. This is the first report of the isolation of one unprecedented compound 4 from Lachnum genus, while all known compounds were also found for the first time from Lachnum. The effects of some isolates (3, 4, 7-9, 10, and 13) on the inhibition of nitric oxide (NO) production in lipopolysaccharide (LPS)-activated RAW 264.7 murine macrophages were also evaluated. Several compounds exhibited weak inhibitory activity on lipopolysaccharide (LPS)-stimulated NO production in RAW 264.7 macrophages. PMID- 27618021 TI - Pharmacogenomics in Pediatric Oncology: Review of Gene-Drug Associations for Clinical Use. AB - During the 3rd congress of the European Society of Pharmacogenomics and Personalised Therapy (ESPT) in Budapest in 2015, a preliminary meeting was held aimed at establishing a pediatric individualized treatment in oncology and hematology committees. The main purpose was to facilitate the transfer and harmonization of pharmacogenetic testing from research into clinics, to bring together basic and translational research and to educate health professionals throughout Europe. The objective of this review was to provide the attendees of the meeting as well as the larger scientific community an insight into the compiled evidence regarding current pharmacogenomics knowledge in pediatric oncology. This preliminary evaluation will help steer the committee's work and should give the reader an idea at which stage researchers and clinicians are, in terms of personalizing medicine for children with cancer. From the evidence presented here, future recommendations to achieve this goal will also be suggested. PMID- 27618027 TI - Cellular Metabolomics Revealed the Cytoprotection of Amentoflavone, a Natural Compound, in Lipopolysaccharide-Induced Injury of Human Umbilical Vein Endothelial Cells. AB - Amentoflavone is one of the important bioactive flavonoids in the ethylacetate extract of "Cebaiye", which is a blood cooling and hematostatic herb in traditional Chinese medicine. The previous work in our group has demonstrated that the ethylacetate extract of Cebaiye has a notable antagonistic effect on the injury induced by lipopolysaccharide (LPS) to human umbilical vein endothelial cells (HUVECs). The present investigation was designed to assess the effects and possible mechanism of cytoprotection of amentoflavone via metabolomics. Ultra performance liquid chromatography/quadrupole time of flight-mass spectrometry (UPLC/QTOF-MS) coupled with multivariate data analysis was used to characterize the variations in the metabolites of HUVECs in response to exposure to LPS and amentoflavone treatment. Seven putative metabolites (glycine, argininosuccinic acid, putrescine, ornithine, spermidine, 5-oxoproline and dihydrouracil) were discovered in cells incubated with LPS and/or amentoflavone. Functional pathway analysis uncovered that the changes of these metabolites related to various significant metabolic pathways (glutathione metabolism, arginine and proline metabolism, beta-alanine metabolism and glycine, serine and threonine metabolism), which may explain the potential cytoprotection function of amentoflavone. These findings also demonstrate that cellular metabolomics through UPLC/QTOF-MS is a powerful tool for detecting variations in a range of intracellular compounds upon toxin and/or drug exposure. PMID- 27618028 TI - Early Prediction of Therapy Response to Abiraterone Acetate Using PSA Subforms in Patients with Castration Resistant Prostate Cancer. AB - The purpose of this study was to evaluate the prognostic ability of early changes of total prostate specific antigen (tPSA), free PSA (fPSA), [-2]proPSA and the Prostate Health Index (PHI) following initiation of Abiraterone-therapy in men with castration resistant prostate cancer (mCRPC). In 25 patients, PSA-subforms were analyzed before and at 8-12 weeks under therapy as prognosticators of progression-free-survival (PFS) and overall survival (OS). Comparing patients with a PFS < vs. >=12 months by using Mann-Whitney-Wilcoxon Tests, the relative median-change of tPSA (-0.1% vs. -86.8%; p = 0.02), fPSA (12.1% vs. -55.3%; p = 0.03) and [-2]proPSA (8.1% vs. -59.3%; p = 0.05) differed significantly. For men with <= vs. >15 months of OS there was a non-significant trend for a difference in the relative-median-change of fPSA (17.0% vs. -46.3%; p = 0.06). In Kaplan Meier analyses, declining fPSA and [-2]proPSA were associated with a longer median PFS (13 months, 95% confidence interval (CI): 9.6-16.4 vs. 10 months, 95% CI: 3.5-16.5; p = 0.11), respectively. Correspondingly, decreasing fPSA and [ 2]proPSA values indicated an OS of 32 months (95% CI: not reached (NR)) compared to 21 months in men with rising values (95% CI: 7.7-34.3; p = 0.14), respectively. We concluded that the addition of fPSA- and [-2]proPSA-changes to tPSA-information might be further studied as potential markers of early Abiraterone response in mCRPC patients. PMID- 27618026 TI - Development of Novel Immunotherapies for Multiple Myeloma. AB - Multiple myeloma (MM) is a disorder of terminally differentiated plasma cells characterized by clonal expansion in the bone marrow (BM). It is the second-most common hematologic malignancy. Despite significant advances in therapeutic strategies, MM remains a predominantly incurable disease emphasizing the need for the development of new treatment regimens. Immunotherapy is a promising treatment modality to circumvent challenges in the management of MM. Many novel immunotherapy strategies, such as adoptive cell therapy and monoclonal antibodies, are currently under investigation in clinical trials, with some already demonstrating a positive impact on patient survival. In this review, we will summarize the current standards of care and discuss major new approaches in immunotherapy for MM. PMID- 27618030 TI - Digital PCR Panel for Sensitive Hematopoietic Chimerism Quantification after Allogeneic Stem Cell Transplantation. AB - Accurate and sensitive determination of hematopoietic chimerism is a crucial diagnostic measure after allogeneic stem cell transplantation to monitor engraftment and potentially residual disease. Short tandem repeat (STR) amplification, the current "gold standard" for chimerism assessment facilitates reliable accuracy, but is hampered by its limited sensitivity (>=1%). Digital PCR (dPCR) has been shown to combine exact quantification and high reproducibility over a very wide measurement range with excellent sensitivity (routinely <=0.1%) and thus represents a promising alternative to STR analysis. We here aimed at developing a whole panel of digital-PCR based assays for routine diagnostic. To this end, we tested suitability of 52 deletion/insertion polymorphisms (DIPs) for duplex analysis in combination with either a reference gene or a Y-chromosome specific PCR. Twenty-nine DIPs with high power of discrimination and good performance were identified, optimized and technically validated. We tested the newly established assays on retrospective patient samples that were in parallel also measured by STR amplification and found excellent correlation. Finally, a screening plate for initial genotyping with DIP-specific duplex dPCR assays was designed for convenient assay selection. In conclusion, we have established a comprehensive dPCR system for precise and high-sensitivity measurement of hematopoietic chimerism, which should be highly useful for clinical routine diagnostics. PMID- 27618029 TI - Virtual Screening Approaches towards the Discovery of Toll-Like Receptor Modulators. AB - This review aims to summarize the latest efforts performed in the search for novel chemical entities such as Toll-like receptor (TLR) modulators by means of virtual screening techniques. This is an emergent research field with only very recent (and successful) contributions. Identification of drug-like molecules with potential therapeutic applications for the treatment of a variety of TLR regulated diseases has attracted considerable interest due to the clinical potential. Additionally, the virtual screening databases and computational tools employed have been overviewed in a descriptive way, widening the scope for researchers interested in the field. PMID- 27618032 TI - A MicroRNA that Regulates TLR-Mediated Fibrosis. AB - Hepatic damage can be caused by an array of factors which, if sustained, can lead to hepatic fibrosis.[...]. PMID- 27618033 TI - Prognostic Value of Serum Caspase-Cleaved Cytokeratin-18 Levels before Liver Transplantation for One-Year Survival of Patients with Hepatocellular Carcinoma. AB - Cytokeratin (CK)-18 is the major intermediate filament protein in the liver and during hepatocyte apoptosis is cleaved by the action of caspases; the resulting fragments are released into the blood as caspase-cleaved cytokeratin (CCCK)-18. Higher circulating levels of CCCK-18 have been found in patients with hepatocellular carcinoma (HCC) than in healthy controls and than in cirrhotic patients. However, it is unknown whether serum CCCK-18 levels before liver transplantation (LT) in patients with HCC could be used as a prognostic biomarker of one-year survival, and this was the objective of our study with 135 patients. At one year after LT, non-survivors showed higher serum CCCK-18 levels than survivors (p = 0.001). On binary logistic regression analysis, serum CCCK-18 levels >384 U/L were associated with death at one year (odds ratio = 19.801; 95% confidence interval = 5.301-73.972; p < 0.001) after controlling for deceased donor age. The area under the receiver operating characteristic (ROC) curve of serum CCCK-18 levels to predict death at one year was 77% (95% CI = 69%-84%; p < 0.001). The new finding of our study was that serum levels of CCCK-18 before LT in patients with HCC could be used as prognostic biomarker of survival. PMID- 27618034 TI - Glycerin-Induced Conformational Changes in Bombyx mori Silk Fibroin Film Monitored by (13)C CP/MAS NMR and 1H DQMAS NMR. AB - In order to improve the stiff and brittle characteristics of pure Bombyx mori (B. mori) silk fibroin (SF) film in the dry state, glycerin (Glyc) has been used as a plasticizer. However, there have been very limited studies on the structural characterization of the Glyc-blended SF film. In this study, (13)C Cross Polarization/Magic Angle Spinning nuclear magnetic resonance (CP/MAS NMR) was used to monitor the conformational changes in the films by changing the Glyc concentration. The presence of only 5 wt % Glyc in the film induced a significant conformational change in SF where Silk I* (repeated type II beta-turn and no alpha-helix) newly appeared. Upon further increase in Glyc concentration, the percentage of Silk I* increased linearly up to 9 wt % Glyc and then tended to be almost constant (30%). This value (30%) was the same as the fraction of Ala residue within the Silk I* form out of all Ala residues of SF present in B. mori mature silkworm. The 1H DQMAS NMR spectra of Glyc-blended SF films confirmed the appearance of Silk I* in the Glyc-blended SF film. A structural model of Glyc-SF complex including the Silk I* form was proposed with the guidance of the Molecular Dynamics (MD) simulation using 1H-1H distance constraints obtained from the 1H Double-Quantum Magic Angle Spinning (DQMAS) NMR spectra. PMID- 27618035 TI - Polyphenols and Sunburn. AB - Polyphenols are antioxidant molecules found in many foods such as green tea, chocolate, grape seeds, and wine. Polyphenols have antioxidant, anti inflammatory, and antineoplastic properties. Growing evidence suggests that polyphenols may be used for the prevention of sunburns as polyphenols decrease the damaging effects of ultraviolet A (UVA) and ultraviolet B (UVB) radiation on the skin. This review was conducted to examine the evidence for use of topically and orally ingested polyphenols in prevention of sunburns. The PubMed database was searched for studies that examined polyphenols and its effects on sunburns. Of the 27 studies found, 15 met the inclusion criteria. Seven studies were conducted on human subjects and eight on animals (mice and rats). Eleven studies evaluated the effects of topical polyphenols, two studies examined ingested polyphenols, and two studies examined both topical and ingested polyphenols. Polyphenol sources included the following plant origins: green tea, white tea, cocoa, Romanian propolis (RP), Calluna vulgaris (Cv), grape seeds, honeybush, and Lepidium meyenii (maca). Eight studies examined green tea. Overall, based on the studies, there is evidence that polyphenols in both oral and topical form may provide protection from UV damage and sunburn, and thus are beneficial to skin health. However, current studies are limited and further research is necessary to evaluate the efficacy, mechanism of action, and potential side effects of various forms and concentrations of polyphenols. PMID- 27618036 TI - Susceptibility and Immune Defence Mechanisms of Rhynchophorus ferrugineus (Olivier) (Coleoptera: Curculionidae) against Entomopathogenic Fungal Infections. AB - Insects infected with entomopathogenic fungi, experience physiological changes that influence their growth and immune defence. The potential of nine isolates of entomopathogenic fungi was evaluated after determining percent germination and relative conidial hydrophobicity. However, nutritional indices were evaluated after immersing eighth-instar Rhynchophorus ferrugineus larvae into each isolate suspension (1 * 107 conidia/mL). The results showed that isolates B6884 and M9374 had 44.51% and 39.02% higher conidial hydrophobicity compared with isolate I03011 (least virulent). The results of nutritional index assays revealed a significant reduction in growth indices after infection with different isolates. Compared with control, B6884 and M9374 greatly decreased larval growth by reducing the efficacy of conversion of ingested food (36%-47%) and Efficacy of conversion of digested food (50%-63%). Furthermore, only isolate B6884 induced 100% mortality within 12 days. Compared with control, isolate I03011, possessing the lowest conidial hydrophobicity, only reduced 0.29% of the efficacy of conversion of ingested food (ECI) and 0.48% of the efficacy of conversion of digested food (ECD). Similarly, transcriptomic analysis of genes related to the Red palm weevil (RPW) immune response, including pathogen recognition receptors (C-type lectin and endo-beta-1,4-glucanse), signal modulator (Serine protease-like protein), signal transductors (Calmodulin-like protein and EF-hand domain containing protein) and effectors (C-type lysozyme, Cathepsin L., Defensin-like protein, Serine carboxypeptidase, and Thaumatin-like protein), was significantly increased in larval samples infected with B6884 and M9374. These results suggest that for an isolate to be virulent, conidial hydrophobicity and germination should also be considered during pathogen selection, as these factors could significantly impact host growth and immune defence mechanisms. PMID- 27618031 TI - Molecular Imaging of Vulnerable Atherosclerotic Plaques in Animal Models. AB - Atherosclerosis is characterized by intimal plaques of the arterial vessels that develop slowly and, in some cases, may undergo spontaneous rupture with subsequent heart attack or stroke. Currently, noninvasive diagnostic tools are inadequate to screen atherosclerotic lesions at high risk of acute complications. Therefore, the attention of the scientific community has been focused on the use of molecular imaging for identifying vulnerable plaques. Genetically engineered murine models such as ApoE(-/-) and ApoE(-/-)Fbn1C1039G(+/-) mice have been shown to be useful for testing new probes targeting biomarkers of relevant molecular processes for the characterization of vulnerable plaques, such as vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, intercellular adhesion molecule (ICAM)-1, P-selectin, and integrins, and for the potential development of translational tools to identify high-risk patients who could benefit from early therapeutic interventions. This review summarizes the main animal models of vulnerable plaques, with an emphasis on genetically altered mice, and the state of-the-art preclinical molecular imaging strategies. PMID- 27618039 TI - Single-Side Two-Location Spotlight Imaging for Building Based on MIMO Through Wall-Radar. AB - Through-wall-radar imaging is of interest for mapping the wall layout of buildings and for the detection of stationary targets within buildings. In this paper, we present an easy single-side two-location spotlight imaging method for both wall layout mapping and stationary target detection by utilizing multiple input multiple-output (MIMO) through-wall-radar. Rather than imaging for building walls directly, the images of all building corners are generated to speculate wall layout indirectly by successively deploying the MIMO through-wall-radar at two appropriate locations on only one side of the building and then carrying out spotlight imaging with two different squint-views. In addition to the ease of implementation, the single-side two-location squint-view detection also has two other advantages for stationary target imaging. The first one is the fewer multi path ghosts, and the second one is the smaller region of side-lobe interferences from the corner images in comparison to the wall images. Based on Computer Simulation Technology (CST) electromagnetic simulation software, we provide multiple sets of validation results where multiple binary panorama images with clear images of all corners and stationary targets are obtained by combining two single-location images with the use of incoherent additive fusion and two dimensional cell-averaging constant-false-alarm-rate (2D CA-CFAR) detection. PMID- 27618038 TI - Characteristics of Three Thioredoxin Genes and Their Role in Chilling Tolerance of Harvested Banana Fruit. AB - Thioredoxins (Trxs) are small proteins with a conserved redox active site WCGPC and are involved in a wide range of cellular redox processes. However, little information on the role of Trx in regulating low-temperature stress of harvested fruit is available. In this study, three full-length Trx cDNAs, designated MaTrx6, MaTrx9 and MaTrx12, were cloned from banana (Musa acuminata) fruit. Phylogenetic analysis and protein sequence alignments showed that MaTrx6 was grouped to h2 type with a typical active site of WCGPC, whereas MaTrx9 and MaTrx12 were assigned to atypical cys his-rich Trxs (ACHT) and h3 type with atypical active sites of GCAGC and WCSPC, respectively. Subcellular localization indicated that MaTrx6 and MaTrx12 were located in the plasma membrane and cytoplasm, respectively, whereas MaTrx9 showed a dual cytoplasmic and chloroplast localization. Application of ethylene induced chilling tolerance of harvested banana fruit, whereas 1-MCP, an inhibitor of ethylene perception, aggravated the development of chilling injury. RT-qPCR analysis showed that expression of MaTrx12 was up-regulated and down-regulated in ethylene- and 1-MCP-treated banana fruit at low temperature, respectively. Furthermore, heterologous expression of MaTrx12 in cytoplasmic Trx-deficient Saccharomyces cerevisiae strain increased the viability of the strain under H2O2. These results suggest that MaTrx12 plays an important role in the chilling tolerance of harvested banana fruit, possibly by regulating redox homeostasis. PMID- 27618037 TI - In Vitro Assessment of the Expression and T Cell Immunogenicity of the Tumor Associated Antigens BORIS, MUC1, hTERT, MAGE-A3 and Sp17 in Uterine Cancer. AB - BACKGROUND: While immunotherapy moved to the forefront of treatment of various cancers, it remains underexplored for uterine cancer. This might be due to the small patient population with advanced endometrial carcinoma and uterine sarcoma. Data about immunotherapeutic targets are scarce in endometrial carcinoma and lacking in uterine sarcoma. METHODS: Expression of five tumor-associated antigens (TAA) (BORIS, MUC1, hTERT, MAGE-A3 and Sp17) was validated in uterine tumor samples by immunohistochemistry (IHC) and/or quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). TAA immunogenicity was analyzed by determining spontaneous T cell responses towards overlapping peptide pools covering the whole TAA in patient blood. RESULTS: At mRNA level, MAGE-A3 and Sp17 were overexpressed in a minority of patients and BORIS was moderately overexpressed (26% in endometrial carcinoma and 62% in uterine sarcoma). hTERT was overexpressed in the vast majority of tumors. On protein level, MUC1 was upregulated in primary, recurrent and metastatic EMCAR and in metastatic US tumors. hTERT protein was highly expressed in both normal and malignant tissue. Spontaneous TAA-specific T cell responses were detected in a minority of patients, except for hTERT to which T cell responses occurred more frequently. CONCLUSIONS: These data point to MUC1 and hTERT as most suitable targets based on expression levels and T cell immunogenicity for use in immunotherapeutic regimens. PMID- 27618040 TI - Sparse Reconstruction for Temperature Distribution Using DTS Fiber Optic Sensors with Applications in Electrical Generator Stator Monitoring. AB - This paper presents an image reconstruction method to monitor the temperature distribution of electric generator stators. The main objective is to identify insulation failures that may arise as hotspots in the structure. The method is based on temperature readings of fiber optic distributed sensors (DTS) and a sparse reconstruction algorithm. Thermal images of the structure are formed by appropriately combining atoms of a dictionary of hotspots, which was constructed by finite element simulation with a multi-physical model. Due to difficulties for reproducing insulation faults in real stator structure, experimental tests were performed using a prototype similar to the real structure. The results demonstrate the ability of the proposed method to reconstruct images of hotspots with dimensions down to 15 cm, representing a resolution gain of up to six times when compared to the DTS spatial resolution. In addition, satisfactory results were also obtained to detect hotspots with only 5 cm. The application of the proposed algorithm for thermal imaging of generator stators can contribute to the identification of insulation faults in early stages, thereby avoiding catastrophic damage to the structure. PMID- 27618041 TI - Color Change of Phenol Red by Integrated Smart Phone Camera as a Tool for the Determination of Neurotoxic Compounds. AB - The use of a cell phone as a detection system is easy, simple and does not require trained personnel, which is in contrast to standard laboratory instruments. This paper deals with immobilization of acetylcholinesterase (AChE) in a gelatin matrix, and phenol red, as an indicator of AChE activity, is used in order to establish a method that is easily compatible with a camera device. AChE splits acetylcholine into choline and acetic acid, which changes the pH of a medium, resulting in a phenol red color change. The coloration changed in presence of an AChE inhibitor. Measurements were performed on 3D-printed, tube shaped holder, and digital photography, with subsequent analysis of red-green blue (RGB), served for assay purposes. Calibration of AChE inhibitors, tacrine and galantamine, was performed, with limit of detection equal to 1.1 nM and 1.28 uM, respectively. Interferences were also measured, resulting in a proof-of method stability. The method was further successfully validated for the standard Ellman's assay, and verified on murine plasma samples spiked with inhibitors. PMID- 27618042 TI - A Study of Dispersion Compensation of Polarization Multiplexing-Based OFDM-OCDMA for Radio-over-Fiber Transmissions. AB - Chromatic dispersion from optical fiber is the most important problem that produces temporal skews and destroys the rectangular structure of code patterns in the spectra-amplitude-coding-based optical code-division multiple-access (SAC OCDMA) system. Thus, the balance detection scheme does not work perfectly to cancel multiple access interference (MAI) and the system performance will be degraded. Orthogonal frequency-division multiplexing (OFDM) is the fastest developing technology in the academic and industrial fields of wireless transmission. In this study, the radio-over-fiber system is realized by integrating OFDM and OCDMA via polarization multiplexing scheme. The electronic dispersion compensation (EDC) equalizer element of OFDM integrated with the dispersion compensation fiber (DCF) is used in the proposed radio-over-fiber (RoF) system, which can efficiently suppress the chromatic dispersion influence in long-haul transmitted distance. A set of length differences for 10 km-long single-mode fiber (SMF) and 4 km-long DCF is to verify the compensation scheme by relative equalizer algorithms and constellation diagrams. In the simulation result, the proposed dispersion mechanism successfully compensates the dispersion from SMF and the system performance with dispersion equalizer is highly improved. PMID- 27618043 TI - Dispersion Curve Engineering of TiO2/Silver Hybrid Substrates for Enhanced Surface Plasmon Resonance Detection. AB - As surface plasmon resonance (SPR)-based biosensors are well translated into biological, chemical, environmental, and clinical fields, it is critical to further realize stable and sustainable systems, avoiding oxidation susceptibility of metal films-in particular, silver substrates. We report an enhanced SPR detection performance by incorporating a TiO2 layer on top of a thin silver film. A uniform TiO2 film fabricated by electron beam evaporation at room temperature is an effective alternative in bypassing oxidation of a silver film. Based on our finding that the sensor sensitivity is strongly correlated with the slope of dispersion curves, SPR sensing results obtained by parylene film deposition shows that TiO2/silver hybrid substrates provide notable sensitivity improvement compared to a conventional bare silver film, which confirms the possibility of engineering the dispersion characteristic according to the incidence wavelength. The reported SPR structures with TiO2 films enhance the sensitivity significantly in water and air environments and its overall qualitative trend in sensitivity improvement is consistent with numerical simulations. Thus, we expect that our approach can extend the applicability of TiO2-mediated SPR biosensors to highly sensitive detection for biomolecular binding events of low concentrations, while serving a practical and reliable biosensing platform. PMID- 27618044 TI - A Network Coding Based Hybrid ARQ Protocol for Underwater Acoustic Sensor Networks. AB - Underwater Acoustic Sensor Networks (UASNs) have attracted increasing interest in recent years due to their extensive commercial and military applications. However, the harsh underwater channel causes many challenges for the design of reliable underwater data transport protocol. In this paper, we propose an energy efficient data transport protocol based on network coding and hybrid automatic repeat request (NCHARQ) to ensure reliability, efficiency and availability in UASNs. Moreover, an adaptive window length estimation algorithm is designed to optimize the throughput and energy consumption tradeoff. The algorithm can adaptively change the code rate and can be insensitive to the environment change. Extensive simulations and analysis show that NCHARQ significantly reduces energy consumption with short end-to-end delay. PMID- 27618046 TI - Real-Time Robust Tracking for Motion Blur and Fast Motion via Correlation Filters. AB - Visual tracking has extensive applications in intelligent monitoring and guidance systems. Among state-of-the-art tracking algorithms, Correlation Filter methods perform favorably in robustness, accuracy and speed. However, it also has shortcomings when dealing with pervasive target scale variation, motion blur and fast motion. In this paper we proposed a new real-time robust scheme based on Kernelized Correlation Filter (KCF) to significantly improve performance on motion blur and fast motion. By fusing KCF and STC trackers, our algorithm also solve the estimation of scale variation in many scenarios. We theoretically analyze the problem for CFs towards motions and utilize the point sharpness function of the target patch to evaluate the motion state of target. Then we set up an efficient scheme to handle the motion and scale variation without much time consuming. Our algorithm preserves the properties of KCF besides the ability to handle special scenarios. In the end extensive experimental results on benchmark of VOT datasets show our algorithm performs advantageously competed with the top rank trackers. PMID- 27618045 TI - Pretreated Butterfly Wings for Tuning the Selective Vapor Sensing. AB - Photonic nanoarchitectures occurring in the scales of Blue butterflies are responsible for their vivid blue wing coloration. These nanoarchitectures are quasi-ordered nanocomposites which are constituted from a chitin matrix with embedded air holes. Therefore, they can act as chemically selective sensors due to their color changes when mixing volatile vapors in the surrounding atmosphere which condensate into the nanoarchitecture through capillary condensation. Using a home-built vapor-mixing setup, the spectral changes caused by the different air + vapor mixtures were efficiently characterized. It was found that the spectral shift is vapor-specific and proportional with the vapor concentration. We showed that the conformal modification of the scale surface by atomic layer deposition and by ethanol pretreatment can significantly alter the optical response and chemical selectivity, which points the way to the efficient production of sensor arrays based on the knowledge obtained through the investigation of modified butterfly wings. PMID- 27618047 TI - Study of Intrinsic Dissipation Due to Thermoelastic Coupling in Gyroscope Resonators. AB - This paper presents analytical models, as well as numerical and experimental verification of intrinsic dissipation due to thermoelastic loss in tuning-fork resonator. The thermoelastic analytical governing equations are created for resonator vibrating at drive-mode and sense-mode, and thermoelastic vibration field quantities are deduced. Moreover, the theoretical values are verified that coincided well with finite element analysis (FEM) simulation results. Also, the comparison of vibration field quantities is made to investigate the effect of different conditions on resonator thermoelastic vibration behavior. The significant parameters of thermoelastic damping and quality factor are subsequently deduced to analyze the energy dissipation situation in the vibration process. Meanwhile, the corresponding conclusions from other studies are used to verify our theoretical model and numerical results. By comparing with the experimental quality factor, the numerical values are validated. The combination of the theoretical expressions, numerical results and experimental data leads to an important insight into the achievable quality factor value of tuning-fork resonator, namely, that the thermoelastic damping is the main loss mechanism in the micro-comb finger structure and the quality factor varies under different vibration modes. The results demonstrate that the critical geometry dimensions of tuning-fork resonator can be well designed with the assistance of this study. PMID- 27618048 TI - An Optimized Hidden Node Detection Paradigm for Improving the Coverage and Network Efficiency in Wireless Multimedia Sensor Networks. AB - Successful transmission of online multimedia streams in wireless multimedia sensor networks (WMSNs) is a big challenge due to their limited bandwidth and power resources. The existing WSN protocols are not completely appropriate for multimedia communication. The effectiveness of WMSNs varies, and it depends on the correct location of its sensor nodes in the field. Thus, maximizing the multimedia coverage is the most important issue in the delivery of multimedia contents. The nodes in WMSNs are either static or mobile. Thus, the node connections change continuously due to the mobility in wireless multimedia communication that causes an additional energy consumption, and synchronization loss between neighboring nodes. In this paper, we introduce an Optimized Hidden Node Detection (OHND) paradigm. The OHND consists of three phases: hidden node detection, message exchange, and location detection. These three phases aim to maximize the multimedia node coverage, and improve energy efficiency, hidden node detection capacity, and packet delivery ratio. OHND helps multimedia sensor nodes to compute the directional coverage. Furthermore, an OHND is used to maintain a continuous node- continuous neighbor discovery process in order to handle the mobility of the nodes. We implement our proposed algorithms by using a network simulator (NS2). The simulation results demonstrate that nodes are capable of maintaining direct coverage and detecting hidden nodes in order to maximize coverage and multimedia node mobility. To evaluate the performance of our proposed algorithms, we compared our results with other known approaches. PMID- 27618049 TI - A Tagless Indoor Localization System Based on Capacitive Sensing Technology. AB - Accurate indoor person localization is essential for several services, such as assisted living. We introduce a tagless indoor person localization system based on capacitive sensing and localization algorithms that can determine the location with less than 0.2 m average error in a 3 m * 3 m room and has recall and precision better than 70%. We also discuss the effects of various noise types on the measurements and ways to reduce them using filters suitable for on-sensor implementation to lower communication energy consumption. We also compare the performance of several standard localization algorithms in terms of localization error, recall, precision, and accuracy of detection of the movement trajectory. PMID- 27618050 TI - Planar Microwave Sensor for Theranostic Therapy of Organic Tissue Based on Oval Split Ring Resonators. AB - Microwave sensors in medical environments play a significant role due to the contact-less and non-invasive sensing mechanism to determine dielectric properties of tissue. In this work, a theranostic sensor based on Split Ring Resonators (SRRs) is presented that provides two operation modes to detect and treat tumor cells, exemplary in the liver. For the detection mode, resonance frequency changes due to abnormalities are evaluated, and in the treatment mode, microwave ablation is performed. The planar sensor structure can be integrated into a needle like a surgery tool that evokes challenges concerning size limitations and biocompatibility. To meet the size requirements and provide a reasonable operating frequency, properties of oval shaped SRRs are investigated. By elongating the radius of the SRR in one direction, the resonance frequency can be decreased significantly compared to circular SRR by a factor of two below 12 GHz. In order to validate the detection and treatment characteristics of the sensor, full wave simulations and measurements are examined. Clear resonance shifts are detected for loading the sensor structures with phantoms mimicking healthy and malignant tissue. For treatment mode evaluation, ex vivo beef liver tissue was ablated leading to a lesion zone 1.2 cm * 1 cm * 0.3 cm with a three minute exposure of maximum 2.1 W. PMID- 27618051 TI - Channel-Based Key Generation for Encrypted Body-Worn Wireless Sensor Networks. AB - Body-worn sensor networks are important for rescue-workers, medical and many other applications. Sensitive data are often transmitted over such a network, motivating the need for encryption. Body-worn sensor networks are deployed in conditions where the wireless communication channel varies dramatically due to fading and shadowing, which is considered a disadvantage for communication. Interestingly, these channel variations can be employed to extract a common encryption key at both sides of the link. Legitimate users share a unique physical channel and the variations thereof provide data series on both sides of the link, with highly correlated values. An eavesdropper, however, does not share this physical channel and cannot extract the same information when intercepting the signals. This paper documents a practical wearable communication system implementing channel-based key generation, including an implementation and a measurement campaign comprising indoor as well as outdoor measurements. The results provide insight into the performance of channel-based key generation in realistic practical conditions. Employing a process known as key reconciliation, error free keys are generated in all tested scenarios. The key-generation system is computationally simple and therefore compatible with the low-power micro controllers and low-data rate transmissions commonly used in wireless sensor networks. PMID- 27618052 TI - Real-Time Tracking Framework with Adaptive Features and Constrained Labels. AB - This paper proposes a novel tracking framework with adaptive features and constrained labels (AFCL) to handle illumination variation, occlusion and appearance changes caused by the variation of positions. The novel ensemble classifier, including the Forward-Backward error and the location constraint is applied, to get the precise coordinates of the promising bounding boxes. The Forward-Backward error can enhance the adaptation and accuracy of the binary features, whereas the location constraint can overcome the label noise to a certain degree. We use the combiner which can evaluate the online templates and the outputs of the classifier to accommodate the complex situation. Evaluation of the widely used tracking benchmark shows that the proposed framework can significantly improve the tracking accuracy, and thus reduce the processing time. The proposed framework has been tested and implemented on the embedded system using TMS320C6416 and Cyclone III kernel processors. The outputs show that achievable and satisfying results can be obtained. PMID- 27618053 TI - An Indoor Pedestrian Positioning Method Using HMM with a Fuzzy Pattern Recognition Algorithm in a WLAN Fingerprint System. AB - With the rapid development of smartphones and wireless networks, indoor location based services have become more and more prevalent. Due to the sophisticated propagation of radio signals, the Received Signal Strength Indicator (RSSI) shows a significant variation during pedestrian walking, which introduces critical errors in deterministic indoor positioning. To solve this problem, we present a novel method to improve the indoor pedestrian positioning accuracy by embedding a fuzzy pattern recognition algorithm into a Hidden Markov Model. The fuzzy pattern recognition algorithm follows the rule that the RSSI fading has a positive correlation to the distance between the measuring point and the AP location even during a dynamic positioning measurement. Through this algorithm, we use the RSSI variation trend to replace the specific RSSI value to achieve a fuzzy positioning. The transition probability of the Hidden Markov Model is trained by the fuzzy pattern recognition algorithm with pedestrian trajectories. Using the Viterbi algorithm with the trained model, we can obtain a set of hidden location states. In our experiments, we demonstrate that, compared with the deterministic pattern matching algorithm, our method can greatly improve the positioning accuracy and shows robust environmental adaptability. PMID- 27618054 TI - Experimental Study on Rebar Corrosion Using the Galvanic Sensor Combined with the Electronic Resistance Technique. AB - In this paper, a new kind of carbon steel (CS) and stainless steel (SS) galvanic sensor system was developed for the study of rebar corrosion in different pore solution conditions. Through the special design of the CS and SS electronic coupons, the electronic resistance (ER) method and zero resistance ammeter (ZRA) technique were used simultaneously for the measurement of both the galvanic current and the corrosion depth. The corrosion processes in different solution conditions were also studied by linear polarization resistance (LPR) and the measurements of polarization curves. The test result shows that the galvanic current noise can provide detailed information of the corrosion processes. When localized corrosion occurs, the corrosion rate measured by the ER method is lower than the real corrosion rate. However, the value measured by the LPR method is higher than the real corrosion rate. The galvanic current and the corrosion current measured by the LPR method shows linear correlation in chloride containing saturated Ca(OH)2 solution. The relationship between the corrosion current differences measured by the CS electronic coupons and the galvanic current between the CS and SS electronic coupons can also be used to evaluate the localized corrosion in reinforced concrete. PMID- 27618055 TI - RSS-Based Method for Sensor Localization with Unknown Transmit Power and Uncertainty in Path Loss Exponent. AB - The localization of a sensor in wireless sensor networks (WSNs) has now gained considerable attention. Since the transmit power and path loss exponent (PLE) are two critical parameters in the received signal strength (RSS) localization technique, many RSS-based location methods, considering the case that both the transmit power and PLE are unknown, have been proposed in the literature. However, these methods require a search process, and cannot give a closed-form solution to sensor localization. In this paper, a novel RSS localization method with a closed-form solution based on a two-step weighted least squares estimator is proposed for the case with the unknown transmit power and uncertainty in PLE. Furthermore, the complete performance analysis of the proposed method is given in the paper. Both the theoretical variance and Cramer-Rao lower bound (CRLB) are derived. The relationships between the deterministic CRLB and the proposed stochastic CRLB are presented. The paper also proves that the proposed method can reach the stochastic CRLB. PMID- 27618056 TI - Drift Reduction in Pedestrian Navigation System by Exploiting Motion Constraints and Magnetic Field. AB - Pedestrian navigation systems (PNS) using foot-mounted MEMS inertial sensors use zero-velocity updates (ZUPTs) to reduce drift in navigation solutions and estimate inertial sensor errors. However, it is well known that ZUPTs cannot reduce all errors, especially as heading error is not observable. Hence, the position estimates tend to drift and even cyclic ZUPTs are applied in updated steps of the Extended Kalman Filter (EKF). This urges the use of other motion constraints for pedestrian gait and any other valuable heading reduction information that is available. In this paper, we exploit two more motion constraints scenarios of pedestrian gait: (1) walking along straight paths; (2) standing still for a long time. It is observed that these motion constraints (called "virtual sensor"), though considerably reducing drift in PNS, still need an absolute heading reference. One common absolute heading estimation sensor is the magnetometer, which senses the Earth's magnetic field and, hence, the true heading angle can be calculated. However, magnetometers are susceptible to magnetic distortions, especially in indoor environments. In this work, an algorithm, called magnetic anomaly detection (MAD) and compensation is designed by incorporating only healthy magnetometer data in the EKF updating step, to reduce drift in zero-velocity updated INS. Experiments are conducted in GPS denied and magnetically distorted environments to validate the proposed algorithms. PMID- 27618057 TI - Distributed Particle Filter for Target Tracking: With Reduced Sensor Communications. AB - For efficient and accurate estimation of the location of objects, a network of sensors can be used to detect and track targets in a distributed manner. In nonlinear and/or non-Gaussian dynamic models, distributed particle filtering methods are commonly applied to develop target tracking algorithms. An important consideration in developing a distributed particle filtering algorithm in wireless sensor networks is reducing the size of data exchanged among the sensors because of power and bandwidth constraints. In this paper, we propose a distributed particle filtering algorithm with the objective of reducing the overhead data that is communicated among the sensors. In our algorithm, the sensors exchange information to collaboratively compute the global likelihood function that encompasses the contribution of the measurements towards building the global posterior density of the unknown location parameters. Each sensor, using its own measurement, computes its local likelihood function and approximates it using a Gaussian function. The sensors then propagate only the mean and the covariance of their approximated likelihood functions to other sensors, reducing the communication overhead. The global likelihood function is computed collaboratively from the parameters of the local likelihood functions using an average consensus filter or a forward-backward propagation information exchange strategy. PMID- 27618058 TI - Target Tracking Using SePDAF under Ambiguous Angles for Distributed Array Radar. AB - Distributed array radar can improve radar detection capability and measurement accuracy. However, it will suffer cyclic ambiguity in its angle estimates according to the spatial Nyquist sampling theorem since the large sparse array is undersampling. Consequently, the state estimation accuracy and track validity probability degrades when the ambiguous angles are directly used for target tracking. This paper proposes a second probability data association filter (SePDAF)-based tracking method for distributed array radar. Firstly, the target motion model and radar measurement model is built. Secondly, the fusion result of each radar's estimation is employed to the extended Kalman filter (EKF) to finish the first filtering. Thirdly, taking this result as prior knowledge, and associating with the array-processed ambiguous angles, the SePDAF is applied to accomplish the second filtering, and then achieving a high accuracy and stable trajectory with relatively low computational complexity. Moreover, the azimuth filtering accuracy will be promoted dramatically and the position filtering accuracy will also improve. Finally, simulations illustrate the effectiveness of the proposed method. PMID- 27618059 TI - A Small U-Shaped Bending-Induced Interference Optical Fiber Sensor for the Measurement of Glucose Solutions. AB - The study proposes a small U-shaped bending-induced interference optical fiber sensor; this novel sensor is a probe-type sensor manufactured using a mechanical device, a heat source, optical fiber and a packaging module. This probe-type sensor overcomes the shortcomings of conventional optical fibers, including being difficult to repair and a tendency to be influenced by external forces. We manufactured three types of sensors with different curvature radiuses. Specifically, sensors with three radiuses (1.5 mm, 2.0 mm, and 3.0 mm) were used to measure common water and glucose solutions with concentrations of between 6% and 30% (the interval between concentrations was 4%). The results show that the maximal sensitivity was 0.85 dB/% and that the linearly-dependent coefficient was 0.925. The results further show that not only can the small U-shaped bending induced interference optical fiber sensor achieve high sensitivity in the measurement of glucose solutions, but that it can also achieve great stability and repeatability. PMID- 27618060 TI - Sediment Sampling in Estuarine Mudflats with an Aerial-Ground Robotic Team. AB - This paper presents a robotic team suited for bottom sediment sampling and retrieval in mudflats, targeting environmental monitoring tasks. The robotic team encompasses a four-wheel-steering ground vehicle, equipped with a drilling tool designed to be able to retain wet soil, and a multi-rotor aerial vehicle for dynamic aerial imagery acquisition. On-demand aerial imagery, properly fused on an aerial mosaic, is used by remote human operators for specifying the robotic mission and supervising its execution. This is crucial for the success of an environmental monitoring study, as often it depends on human expertise to ensure the statistical significance and accuracy of the sampling procedures. Although the literature is rich on environmental monitoring sampling procedures, in mudflats, there is a gap as regards including robotic elements. This paper closes this gap by also proposing a preliminary experimental protocol tailored to exploit the capabilities offered by the robotic system. Field trials in the south bank of the river Tagus' estuary show the ability of the robotic system to successfully extract and transport bottom sediment samples for offline analysis. The results also show the efficiency of the extraction and the benefits when compared to (conventional) human-based sampling. PMID- 27618061 TI - Fuzzy C-Means Clustering and Energy Efficient Cluster Head Selection for Cooperative Sensor Network. AB - We propose a novel cluster based cooperative spectrum sensing algorithm to save the wastage of energy, in which clusters are formed using fuzzy c-means (FCM) clustering and a cluster head (CH) is selected based on a sensor's location within each cluster, its location with respect to fusion center (FC), its signal to-noise ratio (SNR) and its residual energy. The sensing information of a single sensor is not reliable enough due to shadowing and fading. To overcome these issues, cooperative spectrum sensing schemes were proposed to take advantage of spatial diversity. For cooperative spectrum sensing, all sensors sense the spectrum and report the sensed energy to FC for the final decision. However, it increases the energy consumption of the network when a large number of sensors need to cooperate; in addition to that, the efficiency of the network is also reduced. The proposed algorithm makes the cluster and selects the CHs such that very little amount of network energy is consumed and the highest efficiency of the network is achieved. Using the proposed algorithm maximum probability of detection under an imperfect channel is accomplished with minimum energy consumption as compared to conventional clustering schemes. PMID- 27618062 TI - Fuzzy Sets in Dynamic Adaptation of Parameters of a Bee Colony Optimization for Controlling the Trajectory of an Autonomous Mobile Robot. AB - A hybrid approach composed by different types of fuzzy systems, such as the Type 1 Fuzzy Logic System (T1FLS), Interval Type-2 Fuzzy Logic System (IT2FLS) and Generalized Type-2 Fuzzy Logic System (GT2FLS) for the dynamic adaptation of the alpha and beta parameters of a Bee Colony Optimization (BCO) algorithm is presented. The objective of the work is to focus on the BCO technique to find the optimal distribution of the membership functions in the design of fuzzy controllers. We use BCO specifically for tuning membership functions of the fuzzy controller for trajectory stability in an autonomous mobile robot. We add two types of perturbations in the model for the Generalized Type-2 Fuzzy Logic System to better analyze its behavior under uncertainty and this shows better results when compared to the original BCO. We implemented various performance indices; ITAE, IAE, ISE, ITSE, RMSE and MSE to measure the performance of the controller. The experimental results show better performances using GT2FLS then by IT2FLS and T1FLS in the dynamic adaptation the parameters for the BCO algorithm. PMID- 27618063 TI - Human Movement Recognition Based on the Stochastic Characterisation of Acceleration Data. AB - Human activity recognition algorithms based on information obtained from wearable sensors are successfully applied in detecting many basic activities. Identified activities with time-stationary features are characterised inside a predefined temporal window by using different machine learning algorithms on extracted features from the measured data. Better accuracy, precision and recall levels could be achieved by combining the information from different sensors. However, detecting short and sporadic human movements, gestures and actions is still a challenging task. In this paper, a novel algorithm to detect human basic movements from wearable measured data is proposed and evaluated. The proposed algorithm is designed to minimise computational requirements while achieving acceptable accuracy levels based on characterising some particular points in the temporal series obtained from a single sensor. The underlying idea is that this algorithm would be implemented in the sensor device in order to pre-process the sensed data stream before sending the information to a central point combining the information from different sensors to improve accuracy levels. Intra- and inter-person validation is used for two particular cases: single step detection and fall detection and classification using a single tri-axial accelerometer. Relevant results for the above cases and pertinent conclusions are also presented. PMID- 27618064 TI - A Study of LoRa: Long Range & Low Power Networks for the Internet of Things. AB - LoRa is a long-range, low-power, low-bitrate, wireless telecommunications system, promoted as an infrastructure solution for the Internet of Things: end-devices use LoRa across a single wireless hop to communicate to gateway(s), connected to the Internet and which act as transparent bridges and relay messages between these end-devices and a central network server. This paper provides an overview of LoRa and an in-depth analysis of its functional components. The physical and data link layer performance is evaluated by field tests and simulations. Based on the analysis and evaluations, some possible solutions for performance enhancements are proposed. PMID- 27618065 TI - Therapeutic Potential of Gramicidin S in the Treatment of Root Canal Infections. AB - An intrinsic clindamycin-resistant Enterococcus faecalis, the most common single species present in teeth after failed root canal therapy, often possesses acquired tetracycline resistance. In these cases, root canal infections are commonly treated with Ledermix((r)) paste, which contains demeclocycline, or the new alternative endodontic paste Odontopaste, which contains clindamycin; however, these treatments are often ineffective. We studied the killing activity of the cyclic antimicrobial peptide gramicidin S (GS) against planktonic and biofilm cells of tetracycline-resistant clinical isolates of E. faecalis. The high therapeutic potential of GS for the topical treatment of problematic teeth is based on the rapid bactericidal effect toward the biofilm-forming, tetracycline-resistant E. faecalis. GS reduces the cell number of planktonic cells within 20-40 min at a concentration of 40-80 MUg/mL. It kills the cells of pre-grown biofilms at concentrations of 100-200 MUg/mL, such that no re-growth is possible. The translocation of the peptide into the cell interior and its complexation with intracellular nucleotides, including the alarmon ppGpp, can explain its anti-biofilm effect. The successful treatment of persistently infected root canals of two volunteers confirms the high effectiveness of GS. The broad GS activity towards resistant, biofilm-forming E. faecalis suggests its applications for approval in root canal medication. PMID- 27618066 TI - 1H and (15)N NMR Analyses on Heparin, Heparan Sulfates and Related Monosaccharides Concerning the Chemical Exchange Regime of the N-Sulfo Glucosamine Sulfamate Proton. AB - Heparin and heparan sulfate are structurally related glycosaminoglycans (GAGs). Both GAGs present, although in different concentrations, N-sulfo-glucosamine (GlcNS) as one of their various composing units. The conditional fast exchange property of the GlcNS sulfamate proton in these GAGs has been pointed as the main barrier to its signal detection via NMR experiments, especially 1H-(15)N HSQC. Here, a series of NMR spectra is collected on heparin, heparan sulfate and related monosaccharides. The N-acetyl glucosamine-linked uronic acid types of these GAGs were properly assigned in the 1H-(15)N HSQC spectra. Dynamic nuclear polarization (DNP) was employed in order to facilitate 1D spectral acquisition of the sulfamate (15)N signal of free GlcNS. Analyses on the multiplet pattern of scalar couplings of GlcNS (15)N has helped to understand the chemical properties of the sulfamate proton in solution. The singlet peak observed for GlcNS happens due to fast chemical exchange of the GlcNS sulfamate proton in solution. Analyses on kinetics of alpha-beta anomeric mutarotation via 1H NMR spectra have been performed in GlcNS as well as other glucose-based monosaccharides. 1D 1H and 2D 1H-(15)N HSQC spectra recorded at low temperature for free GlcNS dissolved in a proton-rich solution showed signals from all exchangeable protons, including those belonging to the sulfamate group. This work suits well to the current grand celebration of one-century-anniversary of the discovery of heparin. PMID- 27618068 TI - Preparation of Temozolomide-Loaded Nanoparticles for Glioblastoma Multiforme Targeting-Ideal Versus Reality. AB - Temozolomide (TMZ) is one of the most effective chemotherapeutic agents for glioblastoma multiforme, but the required high administration dose is accompanied by side effects. To overcome this problem and to further improve TMZ's efficacy, targeted delivery of TMZ by using polymeric nanoparticles has been explored. We synthesised the PLGA-PEG-FOL copolymer and attempted encapsulation of TMZ into PLGA-PEG-FOL nanoparticles using the emulsion solvent evaporation method and the nanoprecipitation method. Conjugation of PEG and FOL to PLGA has been reported to be able to increase the delivery of TMZ to the brain as well as targeting the glioma cells. However, despite making numerous modifications to these methods, the loading of TMZ in the nanoparticles only ranged between 0.2% and 2%, and the nanoparticles were between 400 nm and 600 nm in size after freeze-drying. We proceed with determining the release profile of TMZ in phosphate buffered saline (PBS). Our initial data indicated that TMZ was slowly released from the nanoparticles. The metabolite of TMZ rather than the parent compound was detected in PBS. Our study suggests that while PLGA-PEG-FOL can be used as a polymeric or encapsulation material for central delivery of TMZ, a practical and cost effective formulation method is still far from reach. PMID- 27618067 TI - Targeting TRPM2 in ROS-Coupled Diseases. AB - Under pathological conditions such as inflammation and ischemia-reperfusion injury large amounts of reactive oxygen species (ROS) are generated which, in return, contribute to the development and exacerbation of disease. The second member of the transient receptor potential (TRP) melastatin subfamily, TRPM2, is a Ca(2+)-permeable non-selective cation channel, activated by ROS in an ADP ribose mediated fashion. In other words, TRPM2 functions as a transducer that converts oxidative stress into Ca(2+) signaling. There is good evidence that TRPM2 plays an important role in ROS-coupled diseases. For example, in monocytes the influx of Ca(2+) through TRPM2 activated by ROS contributes to the aggravation of inflammation via chemokine production. In this review, the focus is on TRPM2 as a molecular linker between ROS and Ca(2+) signaling in ROS-coupled diseases. PMID- 27618069 TI - TRPV3 in Drug Development. AB - Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP (Transient Receptor Potential) super-family. It is a relatively underexplored member of the thermo-TRP sub-family (Figure 1), however, genetic mutations and use of gene knock-outs and selective pharmacological tools are helping to provide insights into its role and therapeutic potential. TRPV3 is highly expressed in skin, where it is implicated in skin physiology and pathophysiology, thermo sensing and nociception. Gain of function TRPV3 mutations in rodent and man have enabled the role of TRPV3 in skin health and disease to be particularly well defined. Pre-clinical studies provide some rationale to support development of TRPV3 antagonists for therapeutic application for the treatment of inflammatory skin conditions, itch and pain. However, to date, only one compound directed towards block of the TRPV3 receptor (GRC15300) has progressed into clinical trials. Currently, there are no known clinical trials in progress employing a TRPV3 antagonist. PMID- 27618070 TI - A Saponification Method for Chlorophyll Removal from Microalgae Biomass as Oil Feedstock. AB - Microalgae oil is an optimal feedstock for nutraceutical, pharmaceutical and biodiesel production, but its high levels of chlorophyll limit its large-scale application. To date, few effective approaches have been developed to remove chlorophyll from microalgae oil. The main purpose of this study was to present a preprocessing method of algae oil feedstock (Scenedesmus) to remove chlorophyll by saponification. The results showed that 96% of chlorophyll in biomass was removed. High quality orange transparent oil could be extracted from the chlorophyll reduced biomass. Specifically, the proportion of neutral lipids and saturation levels of fatty acids increased, and the pigments composition became carotenoids-based. The critical parameters of chlorophyll reduced biodiesel conformed to the standards of the USA, China and EU. Sodium copper chlorophyllin could be prepared from the bleaching effluent. The results presented herein offer a useful pathway to improve the quality of microalgae oil and reduce the cost of microalgae biodiesel. PMID- 27618071 TI - The Brown Alga Stypopodium zonale (Dictyotaceae): A Potential Source of Anti Leishmania Drugs. AB - This study evaluated the anti-Leishmania amazonensis activity of a lipophilic extract from the brown alga Stypopodium zonale and atomaric acid, its major compound. Our initial results revealed high inhibitory activity for intracellular amastigotes in a dose-dependent manner and an IC50 of 0.27 MUg/mL. Due to its high anti-Leishmania activity and low toxicity toward host cells, we fractionated the lipophilic extract. A major meroditerpene in this extract, atomaric acid, and its methyl ester derivative, which was obtained by a methylation procedure, were identified by nuclear magnetic resonance (NMR) spectroscopy. Both compounds inhibited intracellular amastigotes, with IC50 values of 20.2 MUM (9 MUg/mL) and 22.9 MUM (10 MUg/mL), and selectivity indexes of 8.4 MUM and 11.5 MUM. The leishmanicidal activity of both meroditerpenes was independent of nitric oxide (NO) production, but the generation of reactive oxygen species (ROS) may be at least partially responsible for the amastigote killing. Our results suggest that the lipophilic extract of S. zonale may represent an important source of compounds for the development of anti-Leishmania drugs. PMID- 27618072 TI - Dichotocejpins A-C: New Diketopiperazines from a Deep-Sea-Derived Fungus Dichotomomyces cejpii FS110. AB - Three new diketopiperazines, dichotocejpins A-C (1-3), together with eight known analogues (4-11), were isolated from the culture of the deep-sea sediment derived fungus Dichotomomyces cejpii FS110. Their structures, including absolute configurations, were elucidated by a combination of HRESIMS, NMR, X-ray crystallography, and ECD calculations. Compounds 4-6, 10-11 showed significant cytotoxic activities against MCF-7, NCI-H460, HepG-2, and SF-268 tumor cell lines. Compound 1 exhibited excellent inhibitory activity against alpha glucosidase with an IC50 of 138 MUM. PMID- 27618074 TI - Public Health Adaptation to Climate Change in OECD Countries. AB - Climate change is a major challenge facing public health. National governments play a key role in public health adaptation to climate change, but there are competing views on what responsibilities and obligations this will-or should include in different nations. This study aims to: (1) examine how national-level public health adaptation is occurring in Organization for Economic Cooperation and Development (OECD) countries; (2) examine the roles national governments are taking in public health adaptation; and (3) critically appraise three key governance dimensions of national-level health adaptation-cross-sectoral collaboration, vertical coordination and national health adaptation planning-and identify practical examples suited to different contexts. We systematically reviewed publicly available public health adaptation to climate change documents and webpages by national governments in ten OECD countries using systematic web searches, assessment of self-reporting, and content analysis. Our findings suggest national governments are primarily addressing infectious disease and heat related risks posed by climate change, typically emphasizing capacity building or information-based groundwork initiatives. We find national governments are taking a variety of approaches to public health adaptation to climate change that do not follow expected convergence and divergence by governance structure. We discuss practical options for incorporating cross-sectoral collaboration, vertical coordination and national health adaptation planning into a variety of contexts and identify leaders national governments can look to to inform their public health adaptation planning. Following the adoption of the Paris Agreement and subsequent increased momentum for adaptation, research tracking adaptation is needed to define what health adaptation looks like in practice, reveal insights that can be taken up across states and sectors, and ensure policy orientated learning. PMID- 27618073 TI - Body Pain Intensity and Interference in Adults (45-53 Years Old): A Cross Sectional Survey in Chongqing, China. AB - Culture and national care models matter both in reporting and treatment of pain status. However, most findings on body pain intensity and interference in adults are from Western studies, with little reliable evidence from China. This study aimed to assess body pain intensity and interference and its associations with demographic, socioeconomic characteristics, and health behaviors in adults. A cross-sectional survey was performed to collect data from 1224 adults, who were recruited via multistage stratified random sampling. The SF-36 quality-of-life instrument was used to investigate body pain intensity and interference. Ordinal logistic regression analysis was used in this study. Our results showed that 64.1% of the participants (males: 687; females: 537) reported body pain, and 45.7% of the participants reported body pain interference. Middle-aged respondents who were female, were unmarried/divorced or separated/widowed, had a negative relationship with their family, had poor sleep quality, and were not satisfied with their current living conditions had a higher body pain intensity rating (ordered logistic regression/six-level pain intensity criterion; odds ratios, p < 0.05). Respondents who were unmarried/divorced or separated/widowed, with a low education level, were unemployed, had lower incomes, had a negative relationship with their family, and were not satisfied with their current living conditions had a higher body pain interference rating (ordered logistic regression/five-level pain interference criterion; odds ratios, p < 0.05). In conclusion, an estimated 64.1% of middle-aged adults reported body pain, and 45.7% of middle-aged adults reported body pain interference. These results provide a clue for possible interventions for improving body pain intensity and interference in adults, especially among middle-aged people. These factors should be taken into consideration in the prevention of pain, pain management and treatment planning in order to help relieve the stress of pain among adults. PMID- 27618075 TI - Impact of Diagnostic Practices on the Self-Reported Health of Mothers of Recently Diagnosed Children with ASD. AB - OBJECTIVES: Obtaining a diagnosis of an Autism Spectrum Disorder (ASD) for a child is a pivotal point in developing the treatment plan for the child but can also be regarded as highly stressful by parents. The current study examined the impact of different aspects of the diagnosis process on the self-reported mental health of mothers of children undergoing a diagnosis for ASD in a cross-sectional cohort design. METHODS: One-hundred-fifty-eight mothers of consequently diagnosed children with ASD participated. The severity of the children's ASD and their intellectual functioning was assessed within twelve months of the diagnosis, and the mothers completed a psychometric assessment battery including the Hospital Anxiety and Depression Scale, General Health Questionnaire, and Questionnaire on Resources and Stress. RESULTS: The actual time from first reporting a problem to obtaining a diagnosis, and the speed of the diagnostic process from first to last appointment, were both negatively related to patenting stress. In contrast, mothers' perceptions of the speed and helpfulness of the process were negatively related to levels of anxiety and depression. The number of professionals involved in the process and the perceived coherence of the diagnosis were also negatively related to aspects of mothers' functioning. CONCLUSIONS: Care is needed to help mothers through the diagnostic process with regard to their own functioning. Providing information and help sources throughout the process, while keeping the number of professionals involved to a minimum, may improve the parent perception of the process and reduce the negative impacts of the diagnosis on the family as a whole. PMID- 27618076 TI - Public Health Impact and Economic Costs of Volkswagen's Lack of Compliance with the United States' Emission Standards. AB - The U.S. Environmental Protection Agency (EPA) recently issued a notice of violation against Volkswagen (VW) for installing a defective device in certain models of diesel cars to circumvent emission tests for nitrogen oxides (NOx). We quantified the health and economic impacts of extra NOx emissions attributable to non-compliant vehicles in the U.S. using the EPA's Co-Benefits Risk Assessment model. We estimated that the total extra NOx emitted over one year of operation would result in 5 to 50 premature deaths, 687 to 17,526 work days with restricted activity, and economic costs of $43,479,189 to $423,268,502, based on various assumptions regarding emission scenarios and risks. This study highlights the potential impacts of VW vehicles' lack of compliance on the health and well-being of the U.S. PMID- 27618079 TI - Economic Burden of Hospitalizations for Heat-Related Illnesses in the United States, 2001-2010. AB - Understanding how heat waves affect morbidity and mortality, as well as the associated economic costs, is essential for characterizing the human health impacts of extreme heat under a changing climate. Only a handful of studies have examined healthcare costs associated with exposures to high temperatures. This research explores costs associated with hospitalizations for heat-related illness (HRI) in the United States using the 2001 to 2010 Nationwide Inpatient Sample (NIS). Descriptive statistics of patient data for HRI hospitalizations were examined and costs of hospitalizations were reported using the all-payer inpatient cost-to-charge ratio. Costs were examined using a log-gamma model with patient and hospital characteristics included as fixed effects. Adjusted mean costs were then compared across racial groups. The mean costs of HRI hospitalizations were higher among racial/ethnic minorities compared to Whites, who accounted for almost 65% of all HRI hospitalizations. Observed differences in costs based on income, insurance, and gender were also significant. These results suggest that these populations are suffering disproportionately from health inequity, thus, they could shoulder greater disease and financial burdens due to climate change. These findings may have important implications in understanding the economic impact public health planning and interventions will have on preventing hospitalizations related to extreme heat. PMID- 27618080 TI - The Effects of Intensive Nutrition Education on Late Middle-Aged Adults with Type 2 Diabetes. AB - OBJECTIVE: Many patients with type 2 diabetes find it difficult to maintain good glycemic control. Undesirable glycemic control occurs greatly due to deficiencies of nutritional knowledge and difficulty in obtaining dietary prescriptions. The late middle-aged and elder individuals are the main populations that are affected by type 2 diabetes. The main purpose of this study was to investigate whether intensive nutrition education would make benefits for late middle-aged patients with type 2 diabetes. METHOD: 196 patients between 50 to 65 years old meeting type 2 diabetes criteria and eligible for the program were included in a single blinded, 30-day centralized management of an education program in China. Participants in the program were randomly divided into a usual nutrition education group or an intensive nutrition education group. The usual nutrition education group was used as a control group and received only basic health advice and principles of diabetic diets at the beginning and the end of the study. Participants in the intensive nutrition education group were arranged to receive intensive nutritional lectures about diabetes for 30 days. The primary outcomes were the changes in weight, body mass index (BMI), fasting plasma glucose (FPG), 2-h postprandial plasma glucose (PG), glycosylated hemoglobin (HbA1c), total glycerin (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL c), and low-density lipoprotein cholesterol (LDL-c). RESULTS: After 30 days of intervention, FPG, PG, and HbA1c in the treatment group decreased significantly than the control group (p < 0.05). HbA1c reduced significantly by 0.6% in the intervention group. No significant differences in the change of blood lipids were observed between groups. However, TG, TC, and HDL-c made improvements compared with the baseline in the experimental group. Both groups had a reduction in weight and BMI within groups, especially in intensive nutrition education group. However, there was no statistical significance between groups. CONCLUSIONS: Intensive nutrition education has significant effects on blood glucose control in late middle-aged adults with type 2 diabetes. Intensive education can cultivate good diet habits and increase physical activity, which are important for diabetes patients in the short and long terms. These findings may contribute to improving education methodology and nutrition therapy in patients with type 2 diabetes. PMID- 27618077 TI - Role of Deficient Mismatch Repair in the Personalized Management of Colorectal Cancer. AB - Colorectal cancer (CRC) represents the third most common type of cancer in developed countries and one of the leading causes of cancer deaths worldwide. Personalized management of CRC has gained increasing attention since there are large inter-individual variations in the prognosis and response to drugs used to treat CRC owing to molecular heterogeneity. Approximately 15% of CRCs are caused by deficient mismatch repair (dMMR) characterized by microsatellite instability (MSI) phenotype. The present review is aimed at highlighting the role of MMR status in informing prognosis and personalized treatment of CRC including adjuvant chemotherapy, targeted therapy, and immune checkpoint inhibitor therapy to guide the individualized therapy of CRC. PMID- 27618081 TI - Cotton Dust Exposure and Respiratory Disorders among Textile Workers at a Textile Company in the Southern Part of Benin. AB - The textile industry sector occupies a prominent place in the economy of Benin. It exposes workers to several occupational risks, including exposure to cotton dust. To assess the effect of exposure to cotton dust on the health of workers, this study was initiated and conducted in a Beninese cotton industry company. The objective of the study was to evaluate the respiratory disorders among the textile workers exposed to cotton dust and the cross-sectional study involved 656 subjects exposed to cotton dust and 113 non-exposed subjects. The methods used are mainly based on a survey using a questionnaire of organic dust designed by the International Commission of Occupational Health (ICOH); and on the measures of lung function parameters (FEV1 and FVC). The main results of the different analyzes revealed that subjects exposed to cotton dust have more respiratory symptoms than unexposed subjects (36.9% vs. 21.2%). The prevalence of chronic cough, expectorations, dyspnoea, asthma and chronic bronchitis are 16.8%, 9.8%, 17.3%, 2.6%, and 5.9% respectively among the exposed versus 2.6%, 0.8%, 16.8%, 0% and 0.8% among the unexposed subjects. The prevalence of byssinosis is 44.01%.The prevalence of symptoms is dependent on the sector of activity and the age of the subject. These results should encourage medical interventions and technical prevention especially since the textile industry occupies an important place in the Benin's economy. PMID- 27618082 TI - Medical Waste Disposal Method Selection Based on a Hierarchical Decision Model with Intuitionistic Fuzzy Relations. AB - Although medical waste usually accounts for a small fraction of urban municipal waste, its proper disposal has been a challenging issue as it often contains infectious, radioactive, or hazardous waste. This article proposes a two-level hierarchical multicriteria decision model to address medical waste disposal method selection (MWDMS), where disposal methods are assessed against different criteria as intuitionistic fuzzy preference relations and criteria weights are furnished as real values. This paper first introduces new operations for a special class of intuitionistic fuzzy values, whose membership and non-membership information is cross ratio based ]0, 1[-values. New score and accuracy functions are defined in order to develop a comparison approach for ]0, 1[-valued intuitionistic fuzzy numbers. A weighted geometric operator is then put forward to aggregate a collection of ]0, 1[-valued intuitionistic fuzzy values. Similar to Saaty's 1-9 scale, this paper proposes a cross-ratio-based bipolar 0.1-0.9 scale to characterize pairwise comparison results. Subsequently, a two-level hierarchical structure is formulated to handle multicriteria decision problems with intuitionistic preference relations. Finally, the proposed decision framework is applied to MWDMS to illustrate its feasibility and effectiveness. PMID- 27618078 TI - The Current Status of the Disease Caused by Enterovirus 71 Infections: Epidemiology, Pathogenesis, Molecular Epidemiology, and Vaccine Development. AB - Enterovirus 71 (EV71) infections have a major public health impact in the Asia Pacific region. We reviewed the epidemiology, pathogenesis, and molecular epidemiology of EV71 infection as well as EV71 vaccine development. Previous studies were found using the search terms "enterovirus 71" and "epidemiology" or "pathogenesis" or "molecular epidemiology" or "vaccine" in Medline and PubMed. Articles that were not published in the English language, manuscripts without an abstract, and opinion articles were excluded from the review. The reported epidemiology of cases caused by EV71 infection varied from country to country; seasonal variations in incidence were observed. Most cases of EV71 infection that resulted in hospitalization for complications occurred in children less than five years old. The brainstem was the most likely major target of EV71 infection. The emergence of the EV71 epidemic in the Asia-Pacific region has been associated with the circulation of different genetic lineages (genotypes B3, B4, C1, C2, and C4) that appear to be undergoing rapid evolutionary changes. The relationship between the gene structure of the EV71 virus and the factors that ensure its survival, circulation, and evasion of immunity is still unknown. EV71 infection has emerged as an important global public health problem. Vaccine development, including the development of inactivated whole-virus live attenuated, subviral particles, and DNA vaccines, has been progressing. PMID- 27618083 TI - Household Air Pollution Intervention Implications: Findings from Qualitative Studies and a Field Trial of Clean Cookstoves in Two Rural Villages in India. AB - Exposure to household air pollution is estimated to be the 3rd largest contributor to the global burden of disease and the largest contributor in South Asia. Unacceptability of improved cook stoves by the intended user has been identified as a crucial factor hindering uptake and sustained use. We conducted a qualitative study to understand the socio-cultural factors that influence acceptance of improved cookstoves and conducted a systematic field trial in two rural villages in Maharashtra, India. The qualitative study used semi-structured in-depth interviews and focus group discussions. We included women primarily responsible for household cooking, their husbands, senior women in their households, and community health workers. We also conducted kitchen observations. The results indicated low awareness and knowledge of the health risks associated with traditional cookstove use although high prevalence of household air pollution (HAP) exposure symptoms among all groups. Women were resigned to using traditional cookstoves although they did not like them. The field trial findings were dominated by responses concerned with convenience and health advantages. We identify important issues to be considered when introducing an improved cookstove programme that will increase acceptability and potentially sustained used of improved cookstoves. PMID- 27618084 TI - Mortality and Burden of Disease Attributable to Cigarette Smoking in Qingdao, China. AB - In China, smoking is the leading preventable cause of deaths by a disease. Estimating the disease burden attributable to smoking contributes to an evaluation of the adverse impact of smoking. To aid in policy change and implementation, this study estimated the population-attributable fractions (PAFs) of smoking, the all-cause mortality and the loss of life expectancy attributable to smoking in 2014 of Qingdao. PAFs were calculated using the smoking impact ratio (SIR) or current smoking rate (P) and relative risk (RR). We determined the smoking-attributable mortality by multiplying the smoking-attributable fraction by the total mortality. This study used the method of an abridged life table to calculate the loss of life expectancy caused by smoking. Smoking caused about 8635 deaths (6883 males, 1752 females), and accounted for 16% of all deaths; 22% in males and 8% in females. The leading causes of deaths attributable to smoking were lung cancer (38%), ischemic heart disease (19%) and chronic obstructive pulmonary disease (COPD, 12%). The PAF for all causes was 22%; 30% in males and 10% in females. Tobacco use may cause a reduction of about 2.01 years of the loss of life expectancy; 3 years in males and 0.87 years in females. The findings highlight the need for taking effective measures to prevent initiation and induce cessation. PMID- 27618085 TI - Disadvantaged Parents' Engagement with a National Secondhand Smoke in the Home Mass Media Campaign: A Qualitative Study. AB - Mass media campaigns can be effective in tobacco control but may widen health inequalities if they fail to engage disadvantaged smokers. This qualitative study explored how parents with young children living in disadvantaged circumstances engaged with a national campaign which aimed to raise awareness of the importance of smokefree homes. Individual semi-structured interviews were carried out with 17 parents before and after the Scottish 2014 "Right Outside" mass media campaign. A conceptual framework exploring meaningful exposure (recall and understanding), motivational responses (protecting children from secondhand smoke (SHS)) and opportunities to act (barriers) was used to thematically analyse the findings. Campaign recall and engagement, and motivation to protect children were high. Parents identified with the dramatized scenario and visual impact of SHS harm to children in the TV advertisement. Some reported changed smoking practices. However, supervising young children in limited accommodation when caring alone constrained opportunities to smoke outside. Instead, parents described actions other than smoking outside that they had taken or were planning to take to create smokefree homes. Mass media campaigns using emotive, real-life circumstances can be effective in engaging parents about SHS. However, the behavioural impact may be limited because of difficult home environments and circumstances. PMID- 27618086 TI - Developing Responsive Indicators of Indigenous Community Health. AB - How health is defined and assessed is a priority concern for Indigenous peoples due to considerable health risks faced from environmental impacts to homelands, and because what is "at risk" is often determined without their input or approval. Many health assessments by government agencies, industry, and researchers from outside the communities fail to include Indigenous definitions of health and omit basic methodological guidance on how to evaluate Indigenous health, thus compromising the quality and consistency of results. Native Coast Salish communities (Washington State, USA) developed and pilot-tested a set of Indigenous Health Indicators (IHI) that reflect non-physiological aspects of health (community connection, natural resources security, cultural use, education, self-determination, resilience) on a community scale, using constructed measures that allow for concerns and priorities to be clearly articulated without releasing proprietary knowledge. Based on initial results from pilot-tests of the IHI with the Swinomish Indian Tribal Community (Washington State, USA), we argue that incorporation of IHIs into health assessments will provide a more comprehensive understanding of Indigenous health concerns, and assist Indigenous peoples to control their own health evaluations. PMID- 27618087 TI - Evaluation of a Home-Based Environmental and Educational Intervention to Improve Health in Vulnerable Households: Southeastern Pennsylvania Lead and Healthy Homes Program. AB - This evaluation examined whether participation in a home-based environmental educational intervention would reduce exposure to health and safety hazards and asthma-related medical visits. The home intervention program focused on vulnerable, low-income households, where children had asthma, were at risk for lead poisoning, or faced multiple unsafe housing conditions. Home visitors conducted two home visits, two months apart, consisting of an environmental home assessment, Healthy Homes education, and distribution of Healthy Homes supplies. Measured outcomes included changes in participant knowledge and awareness of environmental home-based hazards, rate of children's asthma-related medical use, and the presence of asthma triggers and safety hazards. Analysis of 2013-2014 baseline and post-intervention program data for a cohort of 150 families revealed a significantly lower three-month rate (p < 0.05) of children's asthma-related doctor visits and hospital admissions at program completion. In addition, there were significantly reduced reports of the presence of home-based hazards, including basement or roof leaks (p = 0.011), plumbing leaks (p = 0.019), and use of an oven to heat the home (p < 0.001). Participants' pre- and post- test scores showed significant improvement (p < 0.05) in knowledge and awareness of home hazards. Comprehensive home interventions may effectively reduce environmental home hazards and improve the health of asthmatic children in the short term. PMID- 27618088 TI - Effect of a Nutritional Intervention in Athlete's Body Composition, Eating Behaviour and Nutritional Knowledge: A Comparison between Adults and Adolescents. AB - The objective of the present study is to evaluate and compare the effect of a nutritional intervention between adolescent and adult. In a before and after quasi-experimental clinical study, 32 athletes (21 adults, age range 20-32 years; 11 adolescents, age range: 12-19 years) participated in a nutritional counselling consisting of four consultations separated by an interval of 45 to 60 days. The athlete's eating behaviour, body composition and nutrition knowledge were evaluated at the beginning and at the end of the protocol. Both groups increased lean body mass and nutritional knowledge. Adolescents increased their mid-arm muscle circumference and improved meal frequency, and daily water intake. Athletes of both groups improved their ingestion of vegetables and fruits and decreased the ingestion of sweets and oils. Adolescents showed a higher prevalence of individuals that remained within or approached to the recommendations of sweets. This is the first study to evaluate and compare the effect of a nutritional intervention between adolescent and adult athletes body composition, eating behaviour and nutritional knowledge. The nutritional counselling has been effective in promoting beneficial changes on the athlete's eating behaviour, nutritional knowledge and body composition, however, some healthy changes were only experienced by adolescents, especially in the frequency of meals and the intake of sweets. PMID- 27618089 TI - The Diet Quality of Competitive Adolescent Male Rugby Union Players with Energy Balance Estimated Using Different Physical Activity Coefficients. AB - OBJECTIVES: The aims of the current study were to comprehensively assess the dietary intakes and diet quality of a sample of Australian competitive adolescent rugby union players and compare these intakes with National and Sports Dietitians Association (SDA) Recommendations for adolescent athletes. A secondary aim investigated applying different physical activity level (PAL) coefficients to determine total energy expenditure (TEE) in order to more effectively evaluate the adequacy of energy intakes. DESIGN: Cross-sectional. METHODS: Anthropometrics and dietary intakes were assessed in 25 competitive adolescent male rugby union players (14 to 18 years old). Diet was assessed using the validated Australian Eating Survey (AES) food frequency questionnaire and diet quality was assessed through the Australian Recommended Food Score. RESULTS: The median dietary intakes of participants met national recommendations for percent energy (% E) from carbohydrate, protein and total fat, but not carbohydrate intake when evaluated as g/day as proposed in SDA guidelines. Median intakes of fibre and micronutrients including calcium and iron also met national recommendations. Overall diet quality was classified as 'good' with a median diet quality score of 34 (out of a possible 73); however, there was a lack of variety within key food groups including carbohydrates and proteins. Non-core food consumption exceeded recommended levels at 38% of the daily total energy intake, with substantial contributions from takeaway foods and sweetened beverages. A PAL coefficient of 1.2-1.4 was found to best balance the energy intakes of these players in their pre-season. CONCLUSIONS: Adolescent rugby players met the percent energy recommendations for macronutrients and attained an overall 'good' diet quality score. However, it was identified that when compared to specific recommendations for athletes, carbohydrate intakes were below recommendations and these players in their pre-season reported high consumption of non-core foods, particularly sugar sweetened drinks and low intakes of vegetables. PMID- 27618090 TI - Short- and Long-Term Effects of Wholegrain Oat Intake on Weight Management and Glucolipid Metabolism in Overweight Type-2 Diabetics: A Randomized Control Trial. AB - Glycemic control and weight reduction are primary goals for the management of overweight and obese type 2 diabetes mellitus (T2DM). Effective management cannot be achieved without an appropriate diet. Our study aimed to evaluate the short- and long-term effects of oat intake and develop a reasonable dietary plan for overweight T2DM patients. A randomized control trial, registered under ClinicalTrials.gov (Identification code: NCT01495052), was carried out among adult T2DM patients. A subgroup of 298 overweight subjects was selected and received a 30-day centralized intervention and 1-year free-living follow-up. Participants were randomly allocated to one of the following four groups. The usual care group (n = 60) received no intervention; the healthy diet group (n = 79) received a low-fat and high-fiber diet ("healthy diet"); the 50 g-oats group (n = 80) and 100 g-oats group (n = 79) received the "healthy diet" with the same amount of cereals replaced by 50 g and 100 g oats respectively. Anthropometric, blood glycemic and lipid variables were measured. For the 30-day intervention, significant differences in the changes of FPG (fasting plasma glucose), PPG (postprandial plasma glucose), HbA1c (glycosylated hemoglobin), HOMA-IR (homeostasis model assessment of insulin resistance), TC (total cholesterol), TG (total triglycerides), and LDL-c (low-density lipoprotein cholesterol) were observed among the four groups. Compared to the healthy diet group, the 50 g-oats group had a bigger reduction in PPG (mean difference (MD): -1.04 mmol/L; 95% CI: 2.03, -0.05) and TC (MD: -0.24 mmol/L; 95% CI: -0.47, -0.01); the 100 g-oats group had a bigger reduction in PPG (MD: -1.48 mmol/L; 95% CI: -2.57, -0.39), HOMA-IR (MD: -1.77 mU.mol/L2; 95% CI: -3.49, -0.05), TC (MD: -0.33 mmol/L; 95% CI: -0.56, -0.10) and LDL-c (MD: -0.22 mmol/L; 95% CI: -0.41, -0.03). In the 1 year follow-up, greater effects in reducing weight (MD: -0.89 kg; 95% CI: -1.56, 0.22), HbA1c (MD: -0.64%; 95% CI: -1.19, -0.09) and TG (MD: -0.70 mmol/L; 95% CI: -1.11, -0.29) were observed in the 100 g-oats group. In conclusion, short- and long-term oat intake had significant effects on controlling hyperglycemia, lowering blood lipid and reducing weight. Our study provided some supportive evidence for recommending oat as a good whole grain selection for overweight diabetics. PMID- 27618091 TI - Supplemental Protein during Heavy Cycling Training and Recovery Impacts Skeletal Muscle and Heart Rate Responses but Not Performance. AB - The effects of protein supplementation on cycling performance, skeletal muscle function, and heart rate responses to exercise were examined following intensified (ICT) and reduced-volume training (RVT). Seven cyclists performed consecutive periods of normal training (NT), ICT (10 days; average training duration 220% of NT), and RVT (10 days; training duration 66% of NT). In a crossover design, subjects consumed supplemental carbohydrate (CHO) or an equal amount of carbohydrate with added protein (CP) during and following each exercise session (CP = +0.94 g/kg/day protein during ICT; +0.39 g/kg/day during RVT). A 30 kilometer time trial performance (following 120 min at 50% Wmax) was modestly impaired following ICT (+2.4 +/- 6.4% versus NT) and returned to baseline levels following RVT (-0.7 +/- 4.5% versus NT), with similar responses between CHO and CP. Skeletal muscle torque at 120 deg/s benefited from CP, compared to CHO, following ICT. However, this effect was no longer present at RVT. Following ICT, muscle fiber cross-sectional area was increased with CP, while there were no clear changes with CHO. Reductions in constant-load heart rates (at 50% Wmax) following RVT were likely greater with CP than CHO (-9 +/- 9 bpm). Overall it appears that CP supplementation impacted skeletal muscle and heart rate responses during a period of heavy training and recovery, but this did not result in meaningful changes in time trial performance. PMID- 27618092 TI - Water and Beverage Consumption among Children Aged 4-13 Years in Lebanon: Findings from a National Cross-Sectional Study. AB - This study evaluates total water intake (TWI) from plain water, beverages and foods among Lebanese children and compares TWI to dietary reference intakes (DRIs). In a national cross-sectional survey, data on demographic, socioeconomic, anthropometric, and physical activity characteristics were obtained from 4 to 13 year-old children (n = 752). Food and beverage consumption patterns were assessed using a validated food-frequency questionnaire. TWI was estimated at 1651 mL/day, with beverages contributing 72% of the TWI compared to 28% from foods. Beverages with the highest contribution to TWI included plain water, fruit juice and soda. A significantly higher proportion of 9-13-year-old children failed to meet the DRIs compared to 4-8 years old (92%-98% vs. 74%). Gender differentials were observed with a significantly higher proportion of boys meeting the DRIs compared to girls. The water to energy ratio ranged between 0.84 and 0.87, which fell short of meeting the desirable recommendations. In addition, children from higher socioeconomic status had higher intakes of water from milk and bottled water, coupled with lower water intakes from sodas. The study findings show an alarming high proportion of Lebanese children failing to meet TWI recommendations, and call for culture-specific interventions to instill healthy fluid consumption patterns early in life. PMID- 27618094 TI - Evidence Synthesis and Translation for Nutrition Interventions to Combat Micronutrient Deficiencies with Particular Focus on Food Fortification. AB - Over two billion people suffer from micronutrient deficiencies. Food fortification is a prominent nutrition intervention to combat such deficiencies; however, its effectiveness, risks, and ethical implications vary depending on the contexts associated with the deficiency it is addressing and the circumstances with its implementation. The aim of this research was to analyse the profile of nutrition interventions for combating micronutrient deficiency with particular focus on food fortification reported in existing systematic reviews (SRs), guidelines and policy statements, and implementation actions for nutrition. A review of secondary data available from online databases of SRs, guidelines and policy statements, and implementation actions, categorised as either "nutrition specific interventions" (NSpI) or "nutrition-sensitive interventions" (NSeI), was conducted. Currently, there is evidence available for a diversity of food fortification topics, and there has been much translation into action. Indeed, food fortification and micronutrient supplementation interventions and NSpI more broadly dominate the profile of interventions for which there were SRs, guidelines, and policy statements available. The findings demonstrate that, although there is a rational linear relationship between evidence synthesis and translation in formulating policy and actions to combat micronutrient deficiencies, the various nutrition interventions available to help combat micronutrient deficiencies are not equally represented in the evidence synthesis and translation processes. Effective and safe policies and actions to combat micronutrient deficiencies require decisions to be informed from a body of evidence that consists of evidence from a variety of interventions. Into the future, investment in making available a higher number of SRs, guidelines and policy statements, and actions of NSeI is indicated. PMID- 27618093 TI - Polydextrose: Physiological Function, and Effects on Health. AB - Polydextrose (PDX) is a non-digestible oligosaccharide used widely across most sectors of the food industry. It is a randomly linked glucose oligomer containing small amounts of sorbitol and citric acid. The random bonds in PDX prevent mammalian digestive enzymes from readily hydrolyzing the molecule and it has a reported energy value of 1 kcal/g. These properties have led to the acceptance in many countries that PDX provides similar physiological effects as other dietary fibers and has shown prebiotic potential. Dietary intervention with prebiotics has been shown to selectively stimulate the growth and/or activity of one or a limited number of intestinal bacteria associated with several physiological benefits on health. Therefore, the objective of this review was a survey of the literature on the effect of supplementation with PDX in health, and to list the benefits for maintaining health and/or reducing the development of diseases. PMID- 27618096 TI - Evaluation of an Innovative Method for Calculating Energy Intake of Hospitalized Patients. AB - The purpose of this study was to evaluate a multi-component method for capturing nutrient intake, which used observation, photography, and an innovative computer program. To assess reliability and accuracy, multiple responsible employees (REs) independently conducted nutrient intake assessments on simulated meals; each RE's results relating to energy intake were compared to those from the other REs and to those obtained by pre- and post-meal weighing of the food items. System efficiency was assessed by having REs perform independent assessments on the same set of simulated meals using either the new or traditional hospital method for which the REs had to document each food item served and then find the items in a computer database-steps that were automated in the new method. Interrater reliability for energy intake estimated on clinic wards was excellent (intraclass correlation coefficient = 0.975, 95% CI 0.958 to 0.992) and there was a high level of agreement between the REs' estimates and the true values determined by food weighing; per the method of Bland and Altman the mean difference between the two types of estimates was 0.3 kcal (95% CI, -8.1 to 8.7 kcal) with limits of agreement of -79.5 kcal to 80.1 kcal. Compared to the traditional method, energy intake assessments could be completed using the multi-component method in less than a third of the time. These results indicate the multi-component method is an accurate, reliable, and efficient method of obtaining energy intake assessments for hospitalized patients. PMID- 27618095 TI - Anticancer Efficacy of Polyphenols and Their Combinations. AB - Polyphenols, found abundantly in plants, display many anticarcinogenic properties including their inhibitory effects on cancer cell proliferation, tumor growth, angiogenesis, metastasis, and inflammation as well as inducing apoptosis. In addition, they can modulate immune system response and protect normal cells against free radicals damage. Most investigations on anticancer mechanisms of polyphenols were conducted with individual compounds. However, several studies, including ours, have indicated that anti-cancer efficacy and scope of action can be further enhanced by combining them synergistically with chemically similar or different compounds. While most studies investigated the anti-cancer effects of combinations of two or three compounds, we used more comprehensive mixtures of specific polyphenols and mixtures of polyphenols with vitamins, amino acids and other micronutrients. The mixture containing quercetin, curcumin, green tea, cruciferex, and resveratrol (PB) demonstrated significant inhibition of the growth of Fanconi anemia head and neck squamous cell carcinoma and dose-dependent inhibition of cell proliferation, matrix metalloproteinase (MMP)-2 and -9 secretion, cell migration and invasion through Matrigel. PB was found effective in inhibition of fibrosarcoma HT-1080 and melanoma A2058 cell proliferation, MMP 2 and -9 expression, invasion through Matrigel and inducing apoptosis, important parameters for cancer prevention. A combination of polyphenols (quercetin and green tea extract) with vitamin C, amino acids and other micronutrients (EPQ) demonstrated significant suppression of ovarian cancer ES-2 xenograft tumor growth and suppression of ovarian tumor growth and lung metastasis from IP injection of ovarian cancer A-2780 cells. The EPQ mixture without quercetin (NM) also has shown potent anticancer activity in vivo and in vitro in a few dozen cancer cell lines by inhibiting tumor growth and metastasis, MMP-2 and -9 secretion, invasion, angiogenesis, and cell growth as well as induction of apoptosis. The presence of vitamin C, amino acids and other micronutrients could enhance inhibitory effect of epigallocatechin gallate (EGCG) on secretion of MMPs. In addition, enrichment of NM with quercetin (EPQ mix) enhanced anticancer activity of NM in vivo. In conclusion, polyphenols, especially in combination with other polyphenols or micronutrients, have been shown to be effective against multiple targets in cancer development and progression, and should be considered as safe and effective approaches in cancer prevention and therapy. PMID- 27618097 TI - Effects of Folic Acid on Secretases Involved in Abeta Deposition in APP/PS1 Mice. AB - Alzheimer's disease (AD) is the most common type of dementia. Amyloid-beta protein (Abeta) is identified as the core protein of neuritic plaques. Abeta is generated by the sequential cleavage of the amyloid precursor protein (APP) via the APP cleaving enzyme (alpha-secretase, or beta-secretase) and gamma-secretase. Previous studies indicated that folate deficiency elevated Abeta deposition in APP/PS1 mice, and this rise was prevented by folic acid. In the present study, we aimed to investigate whether folic acid could influence the generation of Abeta by regulating alpha-, beta-, and gamma-secretase. Herein, we demonstrated that folic acid reduced the deposition of Abeta42 in APP/PS1 mice brain by decreasing the mRNA and protein expressions of beta-secretase [beta-site APP-cleaving enzyme 1 (BACE1)] and gamma-secretase complex catalytic component-presenilin 1 (PS1)-in APP/PS1 mice brain. Meanwhile, folic acid increased the levels of ADAM9 and ADAM10, which are important alpha-secretases in ADAM (a disintegrin and metalloprotease) family. However, folic acid has no impact on the protein expression of nicastrin (Nct), another component of gamma-secretase complex. Moreover, folic acid regulated the expression of miR-126-3p and miR-339-5p, which target ADAM9 and BACE1, respectively. Taken together, the effect of folic acid on Abeta deposition may relate to making APP metabolism through non-amyloidogenic pathway by decreasing beta-secretase and increasing alpha-secretase. MicroRNA (miRNA) may involve in the regulation mechanism of folic acid on secretase expression. PMID- 27618099 TI - Effective Botulinum Toxin Injection Guide for Treatment of Temporal Headache. AB - This study involved an extensive analysis of published research on the morphology of the temporalis muscle in order to provide an anatomical guideline on how to distinguish the temporalis muscle and temporalis tendon by observing the surface of the patient's face. Twenty-one hemifaces of cadavers were used in this study. The temporalis muscles were dissected clearly for morphological analysis between the temporalis muscle and tendon. The posterior border of the temporalis tendon was classified into three types: in Type I the posterior border of the temporalis tendon is located in front of reference line L2 (4.8%, 1/21), in Type II it is located between reference lines L2 and L3 (85.7%, 18/21), and in Type III it is located between reference lines L3 and L4 (9.5%, 2/21). The vertical distances between the horizontal line passing through the jugale (LH) and the temporalis tendon along each of reference lines L0, L1, L2, L3, and L4 were 29.7 +/- 6.8 mm, 45.0 +/- 8.8 mm, 37.7 +/- 11.1 mm, 42.5 +/- 7.5 mm, and 32.1 +/- 0.4 mm, respectively. BoNT-A should be injected into the temporalis muscle at least 45 mm vertically above the zygomatic arch. This will ensure that the muscle region is targeted and so produce the greatest clinical effect with the minimum concentration of BoNT-A. PMID- 27618098 TI - A Tricky Trait: Applying the Fruits of the "Function Debate" in the Philosophy of Biology to the "Venom Debate" in the Science of Toxinology. AB - The "function debate" in the philosophy of biology and the "venom debate" in the science of toxinology are conceptually related. Venom systems are complex multifunctional traits that have evolved independently numerous times throughout the animal kingdom. No single concept of function, amongst those popularly defended, appears adequate to describe these systems in all their evolutionary contexts and extant variations. As such, a pluralistic view of function, previously defended by some philosophers of biology, is most appropriate. Venom systems, like many other functional traits, exist in nature as points on a continuum and the boundaries between "venomous" and "non-venomous" species may not always be clearly defined. This paper includes a brief overview of the concept of function, followed by in-depth discussion of its application to venom systems. A sound understanding of function may aid in moving the venom debate forward. Similarly, consideration of a complex functional trait such as venom may be of interest to philosophers of biology. PMID- 27618101 TI - Beyond Ribosomal Binding: The Increased Polarity and Aberrant Molecular Interactions of 3-epi-deoxynivalenol. AB - Deoxynivalenol (DON) is a secondary fungal metabolite and contaminant mycotoxin that is widely detected in wheat and corn products cultivated around the world. Bio-remediation methods have been extensively studied in the past two decades and promising ways to reduce DON-associated toxicities have been reported. Bacterial epimerization of DON at the C3 carbon was recently reported to induce a significant loss in the bio-toxicity of the resulting stereoisomer (3-epi-DON) in comparison to the parental compound, DON. In an earlier study, we confirmed the diminished bio-potency of 3-epi-DON using different mammalian cell lines and mouse models and mechanistically attributed it to the reduced binding of 3-epi DON within the ribosomal peptidyl transferase center (PTC). In the current study and by inspecting the chromatographic behavior of 3-epi-DON and its molecular interactions with a well-characterized enzyme, Fusarium graminearum Tri101 acetyltransferase, we provide the evidence that the C3 carbon epimerization of DON influences its molecular interactions beyond the abrogated PTC binding. PMID- 27618100 TI - Early Activation of MAPK p44/42 Is Partially Involved in DON-Induced Disruption of the Intestinal Barrier Function and Tight Junction Network. AB - Deoxynivalenol (DON), produced by the plant pathogens Fusarium graminearum and Fusarium culmorum, is one of the most common mycotoxins, contaminating cereal and cereal-derived products. Although worldwide contamination of food and feed poses health threats to humans and animals, pigs are particularly susceptible to this mycotoxin. DON derivatives, such as deepoxy-deoxynivalenol (DOM-1), are produced by bacterial transformation of certain intestinal bacteria, which are naturally occurring or applied as feed additives. Intestinal epithelial cells are the initial barrier against these food- and feed-borne toxins. The present study confirms DON-induced activation of MAPK p44/42 and inhibition of p44/42 by MAPK inhibitor U0126 monoethanolate. Influence of DON and DOM-1 on transepithelial electrical resistance (TEER), viability and expression of seven tight junction proteins (TJ), as well as the potential of U0126 to counteract DON-induced effects, was assessed. While DOM-1 showed no effect, DON significantly reduced TEER of differentiated IPEC-J2 and decreased expression of claudin-1 and -3, while leaving claudin-4; ZO-1, -2, and -3 and occludin unaffected. Inhibition of p44/42 counteracted DON-induced TEER decrease and restored claudin-3, but not claudin-1 expression. Therefore, effects of DON on TEER and claudin-3 are at least partially p44/42 mediated, while effects on viability and claudin-1 are likely mediated via alternative pathways. PMID- 27618103 TI - Telomerase Activation in Hematological Malignancies. AB - Telomerase expression and telomere maintenance are critical for cell proliferation and survival, and they play important roles in development and cancer, including hematological malignancies. Transcriptional regulation of the rate-limiting subunit of human telomerase reverse transcriptase gen (hTERT) is a complex process, and unveiling the mechanisms behind its reactivation is an important step for the development of diagnostic and therapeutic applications. Here, we review the main mechanisms of telomerase activation and the associated hematologic malignancies. PMID- 27618104 TI - Mechanisms and Physiological Roles of the CBL-CIPK Networking System in Arabidopsis thaliana. AB - Calcineurin B-like protein (CBL)-CBL-interacting protein kinase (CIPK) network is one of the vital regulatory mechanisms which decode calcium signals triggered by environmental stresses. Although the complicated regulation mechanisms and some novel functions of CBL-CIPK signaling network in plants need to be further elucidated, numerous advances have been made in its roles involved in the abiotic stresses. This review chiefly introduces the progresses about protein interaction, classification and expression pattern of different CBLs and CIPKs in Arabidopsis thaliana, summarizes the physiological roles of CBL-CIPK pathway while pointing out some new research ideas in the future, and finally presents some unique perspectives for the further study. The review might provide new insights into the functional characterization of CBL-CIPK pathway in Arabidopsis, and contribute to a deeper understanding of CBL-CIPK network in other plants or stresses. PMID- 27618106 TI - Clinical Utility of Positron Emission Tomography Magnetic Resonance Imaging (PET MRI) in Gastrointestinal Cancers. AB - Anatomic imaging utilizing both CT (computed tomography) and MRI (magnetic resonance imaging) limits the assessment of cancer metastases in lymph nodes and distant organs while functional imaging like PET (positron emission tomography) scan has its limitation in spatial resolution capacity. Hybrid imaging utilizing PET-CT and PET-MRI are novel imaging modalities that are changing the current landscape in cancer diagnosis, staging, and treatment response. MRI has shown to have higher sensitivity in soft tissue, head and neck pathology, and pelvic disease, as well as, detecting small metastases in the liver and bone compared to CT. Combining MRI with PET allows for detection of metastases that may have been missed with current imaging modalities. In this review, we will examine the clinical utility of FDG PET-MRI in the diagnosis and staging of gastrointestinal cancers with focus on esophageal, stomach, colorectal, and pancreatic cancers. We will also explore its role in treatment response and future directions associated with it. PMID- 27618102 TI - Current Technologies and Recent Developments for Screening of HPV-Associated Cervical and Oropharyngeal Cancers. AB - Mucosal infection by the human papillomavirus (HPV) is responsible for a growing number of malignancies, predominantly represented by cervical cancer and oropharyngeal squamous cell carcinoma. Because of the prevalence of the virus, persistence of infection, and long latency period, novel and low-cost methods are needed for effective population level screening and monitoring. We review established methods for screening of cervical and oral cancer as well as commercially-available techniques for detection of HPV DNA. We then describe the ongoing development of microfluidic nucleic acid-based biosensors to evaluate circulating host microRNAs that are produced in response to an oncogenic HPV infection. The goal is to develop an ideal screening platform that is low-cost, portable, and easy to use, with appropriate signal stability, sensitivity and specificity. Advances in technologies for sample lysis, pre-treatment and concentration, and multiplexed nucleic acid detection are provided. Continued development of these devices provides opportunities for cancer screening in low resource settings, for point-of-care diagnostics and self-screening, and for monitoring response to vaccination or surgical treatment. PMID- 27618107 TI - Modelling the Effect of Diet Composition on Enteric Methane Emissions across Sheep, Beef Cattle and Dairy Cows. AB - Enteric methane (CH 4 ) is a by-product from fermentation of feed consumed by ruminants, which represents a nutritional loss and is also considered a contributor to climate change. The aim of this research was to use individual animal data from 17 published experiments that included sheep ( n = 288), beef cattle ( n = 71) and dairy cows ( n = 284) to develop an empirical model to describe enteric CH 4 emissions from both cattle and sheep, and then evaluate the model alongside equations from the literature. Data were obtained from studies in the United Kingdom (UK) and Australia, which measured enteric CH 4 emissions from individual animals in calorimeters. Animals were either fed solely forage or a mixed ration of forage with a compound feed. The feed intake of sheep was restricted to a maintenance amount of 875 g of DM per day (maintenance level), whereas beef cattle and dairy cows were fed to meet their metabolizable energy (ME) requirement (i.e., production level). A linear mixed model approach was used to develop a multiple linear regression model to predict an individual animal's CH 4 yield (g CH 4 /kg dry matter intake) from the composition of its diet. The diet components that had significant effects on CH 4 yield were digestible organic matter (DOMD), ether extract (EE) (both g/kg DM) and feeding level above maintenance intake: CH 4 (g/kg DM intake) = 0.046 (+/-0.001) * DOMD - 0.113 (+/ 0.023) * EE - 2.47 (+/-0.29) * (feeding level - 1), with concordance correlation coefficient ( CCC ) = 0.655 and RMSPE = 14.0%. The predictive ability of the model developed was as reliable as other models assessed from the literature. These components can be used to predict effects of diet composition on enteric CH 4 yield from sheep, beef and dairy cattle from feed analysis information. PMID- 27618108 TI - Monty Roberts' Public Demonstrations: Preliminary Report on the Heart Rate and Heart Rate Variability of Horses Undergoing Training during Live Audience Events. AB - Effective training of horses relies on the trainer's awareness of learning theory and equine ethology, and should be undertaken with skill and time. Some trainers, such as Monty Roberts, share their methods through the medium of public demonstrations. This paper describes the opportunistic analysis of beat-to-beat (RR) intervals and heart rate variability (HRV) of ten horses being used in Monty Roberts' public demonstrations within the United Kingdom. RR and HRV was measured in the stable before training and during training. The HRV variables standard deviation of the RR interval (SDRR), root mean square of successive RR differences (RMSSD), geometric means standard deviation 1 (SD1) and 2 (SD2), along with the low and high frequency ratio (LF/HF ratio) were calculated. The minimum, average and maximum RR intervals were significantly lower in training (indicative of an increase in heart rate as measured in beats-per-minute) than in the stable ( p = 0.0006; p = 0.01; p = 0.03). SDRR, RMSSD, SD1, SD2 and the LF/HF ratio were all significantly lower in training than in the stable ( p = 0.001; p = 0.049; p = 0.049; p = 0.001; p = 0.01). When comparing the HR and HRV of horses during Join-up ((r)) to overall training, there were no significant differences in any variable with the exception of maximum RR which was significantly lower ( p = 0.007) during Join-up ((r)) , indicative of short increases in physical exertion (canter) associated with this training exercise. In conclusion, training of horses during public demonstrations is a low-moderate physiological, rather than psychological stressor for horses. The physiological stress responses observed within this study were comparable or less to those previously reported in the literature for horses being trained outside of public audience events. Furthermore, there is no evidence that the use of Join-up ((r)) alters HR and HRV in a way to suggest that this training method negatively affects the psychological welfare of horses. PMID- 27618109 TI - Investigation into Deep Brain Stimulation Lead Designs: A Patient-Specific Simulation Study. AB - New deep brain stimulation (DBS) electrode designs offer operation in voltage and current mode and capability to steer the electric field (EF). The aim of the study was to compare the EF distributions of four DBS leads at equivalent amplitudes (3 V and 3.4 mA). Finite element method (FEM) simulations (n = 38) around cylindrical contacts (leads 3389, 6148) or equivalent contact configurations (leads 6180, SureStim1) were performed using homogeneous and patient-specific (heterogeneous) brain tissue models. Steering effects of 6180 and SureStim1 were compared with symmetric stimulation fields. To make relative comparisons between simulations, an EF isolevel of 0.2 V/mm was chosen based on neuron model simulations (n = 832) applied before EF visualization and comparisons. The simulations show that the EF distribution is largely influenced by the heterogeneity of the tissue, and the operating mode. Equivalent contact configurations result in similar EF distributions. In steering configurations, larger EF volumes were achieved in current mode using equivalent amplitudes. The methodology was demonstrated in a patient-specific simulation around the zona incerta and a "virtual" ventral intermediate nucleus target. In conclusion, lead design differences are enhanced when using patient-specific tissue models and current stimulation mode. PMID- 27618105 TI - Functional Annotations of Paralogs: A Blessing and a Curse. AB - Gene duplication followed by mutation is a classic mechanism of neofunctionalization, producing gene families with functional diversity. In some cases, a single point mutation is sufficient to change the substrate specificity and/or the chemistry performed by an enzyme, making it difficult to accurately separate enzymes with identical functions from homologs with different functions. Because sequence similarity is often used as a basis for assigning functional annotations to genes, non-isofunctional gene families pose a great challenge for genome annotation pipelines. Here we describe how integrating evolutionary and functional information such as genome context, phylogeny, metabolic reconstruction and signature motifs may be required to correctly annotate multifunctional families. These integrative analyses can also lead to the discovery of novel gene functions, as hints from specific subgroups can guide the functional characterization of other members of the family. We demonstrate how careful manual curation processes using comparative genomics can disambiguate subgroups within large multifunctional families and discover their functions. We present the COG0720 protein family as a case study. We also discuss strategies to automate this process to improve the accuracy of genome functional annotation pipelines. PMID- 27618110 TI - Deep Brain Stimulation: In Search of Reliable Instruments for Assessing Complex Personality-Related Changes. AB - During the last 25 years, more than 100,000 patients have been treated with Deep Brain Stimulation (DBS). While human clinical and animal preclinical research has shed light on the complex brain-signaling disturbances that underpin e.g., Parkinson's disease (PD), less information is available when it comes to complex psychosocial changes following DBS interventions. In this contribution, we propose to more thoroughly investigate complex personality-related changes following deep brain stimulation through refined and reliable instruments in order to help patients and their relatives in the post-surgery phase. By pursuing this goal, we first outline the clinical importance DBS has attained followed by discussing problematic and undesired non-motor problems that accompany some DBS interventions. After providing a brief definition of complex changes, we move on by outlining the measurement problem complex changes relating to non-motor symptoms currently are associated with. The latter circumstance substantiates the need for refined instruments that are able to validly assess personality-related changes. After providing a brief paragraph with regard to conceptions of personality, we argue that the latter is significantly influenced by certain competencies which themselves currently play only a tangential role in the clinical DBS-discourse. Increasing awareness of the latter circumstance is crucial in the context of DBS because it could illuminate a link between competencies and the emergence of personality-related changes, such as new-onset impulse control disorders that have relevance for patients and their relatives. Finally, we elaborate on the field of application of instruments that are able to measure personality-related changes. PMID- 27618111 TI - Protandim Protects Oligodendrocytes against an Oxidative Insult. AB - Oligodendrocyte damage and loss are key features of multiple sclerosis (MS) pathology. Oligodendrocytes appear to be particularly vulnerable to reactive oxygen species (ROS) and cytokines, such as tumor necrosis factor-alpha (TNF), which induce cell death and prevent the differentiation of oligodendrocyte progenitor cells (OPCs). Here, we investigated the efficacy of sulforaphane (SFN), monomethyl fumarate (MMF) and Protandim to induce Nrf2-regulated antioxidant enzyme expression, and protect oligodendrocytes against ROS-induced cell death and ROS-and TNF-mediated inhibition of OPC differentiation. OLN-93 cells and primary rat oligodendrocytes were treated with SFN, MMF or Protandim resulting in significant induction of Nrf2-driven (antioxidant) proteins heme oygenase-1, nicotinamide adenine dinucleotide phosphate (NADPH): quinone oxidoreductase-1 and p62/SQSTM1, as analysed by Western blotting. After incubation with the compounds, oligodendrocytes were exposed to hydrogen peroxide. Protandim most potently promoted oligodendrocyte cell survival as measured by live/death viability assay. Moreover, OPCs were treated with Protandim or vehicle control prior to exposing them to TNF or hydrogen peroxide for five days, which inhibited OPC differentiation. Protandim significantly promoted OPC differentiation under influence of ROS, but not TNF. Protandim, a combination of five herbal ingredients, potently induces antioxidants in oligodendrocytes and is able to protect oligodendrocytes against oxidative stress by preventing ROS-induced cell death and promoting OPC differentiation. PMID- 27618113 TI - Protein-Based Graphene Biosensors: Optimizing Artificial Chemoreception in Bilayer Lipid Membranes. AB - Proteinaceous moieties are critical elements in most detection systems, including biosensing platforms. Their potential is undoubtedly vast, yet many issues regarding their full exploitation remain unsolved. On the other hand, the biosensor formats with the higher marketability probabilities are enzyme in nature and electrochemical in concept. To no surprise, alternative materials for hosting catalysis within an electrode casing have received much attention lately to demonstrate a catalysis-coated device. Graphene and ZnO are presented as ideal materials to modify electrodes and biosensor platforms, especially in protein based detection. Our group developed electrochemical sensors based on these nanomaterials for the sensitive detection of cholesterol using cholesterol oxidase incorporated in stabilized lipid films. A comparison between the two platforms is provided and discussed. In a broader sense, the not-so-remote prospect of quickly assembling a protein-based flexible biosensing detector to fulfill site-specific requirements is appealing to both university researchers and industry developers. PMID- 27618114 TI - Plasma Vascular Endothelial Growth Factor Concentration and Alveolar Nitric Oxide as Potential Predictors of Disease Progression and Mortality in Idiopathic Pulmonary Fibrosis. AB - BACKGROUND: Declining lung function signifies disease progression in idiopathic pulmonary fibrosis (IPF). Vascular endothelial growth factor (VEGF) concentration is associated with declining lung function in 6 and 12-month studies. Alveolar nitric oxide concentration (CANO) is increased in patients with IPF, however its significance is unclear. This study investigated whether baseline plasma VEGF concentration and CANO are associated with disease progression or mortality in IPF. METHODS: 27 IPF patients were studied (maximum follow-up 65 months). Baseline plasma VEGF concentration, CANO and pulmonary function tests (PFTs) were measured. PFTs were performed the preceding year and subsequent PFTs and data regarding mortality were collected. Disease progression was defined as one of: death, relative decrease of >=10% in baseline forced vital capacity (FVC) % predicted, or relative decrease of >=15% in baseline single breath diffusion capacity of carbon monoxide (TLCO-SB) % predicted. RESULTS: Plasma VEGF concentration was not associated with progression-free survival or mortality. There was a trend towards shorter time to disease progression and death with higher CANO. CANO was significantly higher in patients with previous declining versus stable lung function. CONCLUSION: The role of VEGF in IPF remains uncertain. It may be of value to further investigate CANO in IPF. PMID- 27618115 TI - Adherence to Glaucoma Medications Over 12 Months in Two US Community Pharmacy Chains. AB - This study determined the degree of adherence to medications for glaucoma among patients refilling prescriptions in community pharmacies. METHODS: Data abstracted from the dispensing records for 3615 adult patients (18 years or older, predominantly over 45) receiving glaucoma medications from two retail pharmacy chains (64 stores in total) were analyzed. From a 24-month historic data capture period, the 12-month levels of adherence were determined using standard metrics, the proportion of days covered (PDC) and the medication possession ratio (MPR). The overall 12-month mean PDC was only 57%, and the mean MPR was 71%. Using a criterion by which 80% coverage was considered satisfactory adherence, only 30% had satisfactory overall 12-month PDC coverage, and only 37% had satisfactory overall 12-month MPR coverage. Refill adherence increased with age and was highest in the 65-and-older age group (p < 0.001). Differential adherence was found across medication classes, with the highest satisfactory coverage seen for those taking alpha2-adrenergic agonists (PDC = 36.0%; MPR = 47.6%) down to those taking direct cholinergic agonists (PDC = 25.0%; MPR = 31.2%) and combination products (PDC = 22.7%; MPR = 31.0%). Adherence to glaucoma medications in the community setting, as measured by pharmacy refill data, is very poor and represents a critical target for intervention. Community pharmacists are well positioned to monitor and reinforce adherence in this population. PMID- 27618112 TI - Neutrophils and Granulocytic MDSC: The Janus God of Cancer Immunotherapy. AB - Neutrophils are the most abundant circulating blood cell type in humans, and are the first white blood cells recruited at the inflammation site where they orchestrate the initial immune response. Although their presence at the tumor site was recognized in the 1970s, until recently these cells have been neglected and considered to play just a neutral role in tumor progression. Indeed, in recent years neutrophils have been recognized to play a dual role in tumor development by either assisting the growth, angiogenesis, invasion, and metastasis or by exerting tumoricidal action directly via the secretion of antitumoral compounds, or indirectly via the orchestration of antitumor immunity. Understanding the biology of these cells and influencing their polarization in the tumor micro- and macro-environment may be the key for the development of new therapeutic strategies, which may finally hold the promise of an effective immunotherapy for cancer. PMID- 27618116 TI - Individual Differences in the Post-Illumination Pupil Response to Blue Light: Assessment without Mydriatics. AB - Melanopsin-containing retinal ganglion cells play an important role in the non image forming effects of light, through their direct projections on brain circuits involved in circadian rhythms, mood and alertness. Individual differences in the functionality of the melanopsin-signaling circuitry can be reliably quantified using the maximum post-illumination pupil response (PIPR) after blue light. Previous protocols for acquiring PIPR relied on the use of mydriatics to dilate the light-exposed eye. However, pharmacological pupil dilation is uncomfortable for the participants and requires ophthalmological expertise. Hence, we here investigated whether an individual's maximum PIPR can be validly obtained in a protocol that does not use mydriatics but rather increases the intensity of the light stimulus. In 18 participants (5 males, mean age +/- SD: 34.6 +/- 13.6 years) we evaluated the PIPR after exposure to intensified blue light (550 uW/cm2) provided to an undilated dynamic pupil. The test-retest reliability of the primary PIPR outcome parameter was very high, both between day-to-day assessments (Intraclass Correlation Coefficient (ICC) = 0.85), as well as between winter and summer assessments (ICC = 0.83). Compared to the PIPR obtained with the use of mydriatics and 160 uW/cm2 blue light exposure, the method with intensified light without mydriatics showed almost zero bias according to Bland-Altman plots and had moderate to strong reliability (ICC = 0.67). In conclusion, for PIPR assessments, increasing the light intensity is a feasible and reliable alternative to pupil dilation to relieve the participant's burden and to allow for performance outside the ophthalmological clinic. PMID- 27618118 TI - Structural Properties of Cruciferin and Napin of Brassica napus (Canola) Show Distinct Responses to Changes in pH and Temperature. AB - The two major storage proteins identified in Brassica napus (canola) were isolated and studied for their molecular composition, structural characteristics and the responses of structural features to the changes in pH and temperature. Cruciferin, a complex of six monomers, has a predominantly beta-sheet-containing secondary structure. This protein showed low pH unstable tertiary structure, and distinctly different solubility behaviour with pH when intact in the seed cellular matrix. Cruciferin structure unfolds at pH 3 even at ambient temperature. Temperature-induced structure unfolding was observed above the maximum denaturation temperature of cruciferin. Napin was soluble in a wider pH range than cruciferin and has alpha-helices dominating secondary structure. Structural features of napin showed less sensitivity to the changes in medium pH and temperature. The surface hydrophobicity (S0) and intrinsic fluorescence of tryptophan residue appear to be good indicators of cruciferin unfolding, however they were not the best to demonstrate structural changes of napin. These two storage proteins of B. napus have distinct molecular characteristics, therefore properties and functionalities they provide are contrasting rather than complementary. PMID- 27618117 TI - Inhibition of Bacterial RNase P RNA by Phenothiazine Derivatives. AB - There is a need to identify novel scaffolds and targets to develop new antibiotics. Methylene blue is a phenothiazine derivative, and it has been shown to possess anti-malarial and anti-trypanosomal activities. Here, we show that different phenothiazine derivatives and pyronine G inhibited the activities of three structurally different bacterial RNase P RNAs (RPRs), including that from Mycobacterium tuberculosis, with Ki values in the lower MUM range. Interestingly, three antipsychotic phenothiazines (chlorpromazine, thioridazine, and trifluoperazine), which are known to have antibacterial activities, also inhibited the activity of bacterial RPRs, albeit with higher Ki values than methylene blue. Phenothiazines also affected lead(II)-induced cleavage of bacterial RPR and inhibited yeast tRNA(Phe), indicating binding of these drugs to functionally important regions. Collectively, our findings provide the first experimental data showing that long, noncoding RNAs could be targeted by different phenothiazine derivatives. PMID- 27618119 TI - Interaction Effect between Elevated CO2 and Fertilization on Biomass, Gas Exchange and C/N Ratio of European Beech (Fagus sylvatica L.). AB - The effects of elevated CO2 and interaction effects between elevated CO2 and nutrient supplies on growth and the C/N ratio of European beech (Fagus sylvatica L.) saplings were studied. One-year-old beech saplings were grown in a greenhouse at ambient (385 ppm) and elevated CO2 (770 ppm/950 ppm), with or without fertilization for two growing seasons. In this study, emphasis is placed on the combined fertilization including phosphorus, potassium and nitrogen with two level of elevated CO2. The fertilized plants grown under elevated CO2 had the highest net leaf photosynthesis rate (Ac). The saplings grown under elevated CO2 had a significantly lower stomatal conductance (gs) than saplings grown under ambient air. No interaction effect was found between elevated CO2 and fertilization on Ac. A interaction effect between CO2 and fertilization, as well as between date and fertilization and between date and CO2 was detected on gs. Leaf chlorophyll content index (CCI) and leaf nitrogen content were strongly positively correlated to each other and both of them decreased under elevated CO2. At the end of both growing seasons, stem dry weight was greater under elevated CO2 and root dry weight was not affected by different treatments. No interaction effect was detected between elevated CO2 and nutrient supplies on the dry weight of different plant tissues (stems and roots). However, elevated CO2 caused a significant decrease in the nitrogen content of plant tissues. Nitrogen reduction in the leaves under elevated CO2 was about 10% and distinctly higher than in the stem and root. The interaction effect of elevated CO2 and fertilization on C/N ratio in plants tissues was significant. The results led to the conclusion that photosynthesis and the C/N ratio increased while stomatal conductance and leaf nitrogen content decreased under elevated CO2 and nutrient limited conditions. In general, under nutrient-limited conditions, the plant responses to elevated CO2 were decreased. PMID- 27618120 TI - Early Workplace Intervention to Improve the Work Ability of Employees with Musculoskeletal Disorders in a German University Hospital-Results of a Pilot Study. AB - Health promotion is becoming increasingly important in work life. Healthcare workers seem to be at special risk, experiencing musculoskeletal disorders (MSD); their situation is strongly influenced by demographic changes. The aim of this study is to evaluate the feasibility and outcome of a worksite intervention. In a one-group pretest-posttest design, 118 employees of a hospital were recruited from 2010 to 2011. The raised parameters were satisfaction with the program, work ability (Work Ability Index), and sickness absence (provided by human resource management). Patient-reported questionnaire data was raised at baseline (t1) and after three months (t2). Sickness leave was evaluated in the period six months prior to and six months after the intervention. Means, frequencies, standardized effect sizes (SES), analysis of variance, and regression analysis were carried out. Participants were found to be highly satisfied. Work ability increased with moderate effects (SES = 0.34; p < 0.001) and prognosis of gainful employment (SES = -0.19; p <= 0.047) with small effects. Days of MSD-related sickness absence were reduced by 38.5% after six months. The worksite intervention program is transferable to a hospital setting and integration in occupational health management is recommended. The use of a control group is necessary to demonstrate the effectiveness. PMID- 27618121 TI - Justice and Equity Implications of Climate Change Adaptation: A Theoretical Evaluation Framework. AB - Climate change affects human health, and climate change adaptation aims to reduce these risks through infrastructural, behavioral, and technological measures. However, attributing direct human health effects to climate change adaptation is difficult, causing an ethical dilemma between the need for evidence of strategies and their precautionary implementation before such evidence has been generated. In the absence of conclusive evidence for individual adaptation strategies, alternative approaches to the measurement of adaptation effectiveness need to be developed. This article proposes a theoretical framework and a set of guiding questions to assess effects of adaptation strategies on seven domains of health determinants, including social, economic, infrastructure, institutional, community, environmental, and cultural determinants of health. Its focus on advancing gender equity and environmental justice concurrently with the implementation of health-related adaptation could serve as a template for policymakers and researchers. PMID- 27618122 TI - Review of Positive Psychology Applications in Clinical Medical Populations. AB - This review examines the application of positive psychology concepts in physical health care contexts. Positive psychology aims to promote well-being in the general population. Studies identifying character strengths associated with well being in healthy populations are numerous. Such strengths have been classified and Positive Psychology Interventions (PPIs) have been created to further develop these strengths in individuals. Positive psychology research is increasingly being undertaken in health care contexts. The review identified that most of this research involves measuring character strengths and their association with health outcomes in patients with a range of different conditions, similar to the position in positive psychology research on non-clinical populations. More recently, PPIs are beginning to be applied to clinical populations with physical health problems and this research, although relatively scarce, is reviewed here for cancer, coronary heart disease, and diabetes. In common with PPIs being evaluated in the general population, high quality studies are scarce. Applying PPIs to patients with serious health conditions presents significant challenges to health psychologists. They must ensure that patients are dealt with appropriately and ethically, given that exaggerated claims for PPIs are made on the internet quite frequently. This is discussed along with the need for more high quality research. PMID- 27618124 TI - Phosphine-Triggered Selectivity Switch in Silver-Catalyzed o Alkynylbenzohydroxamic Acid Cycloisomerizations. AB - A silver-catalyzed cycloisomerization reaction of a series of o alkynylbenzohydroxamic acids is reported. Several 5-exo-dig and 6-endo-dig modes of cyclization were observed with the nitrogen or oxygen atoms of the amide group acting as nucleophiles. The selectivity was strongly dependent on the silver salt used and on the presence of triphenylphosphine as an additive. Indeed, while the use of Ag2O at room temperature allowed the isolation of isobenzofuran-1-one oximes (7 compounds, 48-92% yield), [Ag(Im)]n with the concomitant addition of 2 equiv of PPh3 led to a switch in selectivity and to a family of isoindolin-1-ones (10 compounds, 59-87%). PMID- 27618126 TI - A new method of measuring shoulder hand behind back movement: Reliability, values in symptomatic and asymptomatic people, effect of hand dominance, and side-to side variability. AB - Shoulder hand behind back (HBB) range of motion (ROM) is a useful measure of impairment and treatment outcome. The purpose of this repeated measures study was to identify inter- and intra-rater reliability, of a new simplified method of measuring HBB ROM. Two experienced raters measured HBB ROM with a bubble inclinometer on 25 people (aged 42-75 years, 14 female) with unilateral shoulder dysfunction and 25 age- and gender-matched asymptomatic subjects on two different occasions. Statistical analysis included calculation of intra-class correlation coefficients (ICCs), minimal detectable change (MDC), standard error of measurement (SEM), Pearson correlation coefficient (r), coefficient of determination (R(2)), and the lower bound score. Mean HBB ROM was 108.6 degrees (SD = 16.3) and 23.9 degrees (SD = 10.5) on the pain-free and symptomatic side, respectively. Both intra-rater and inter-rater reliability were high (ICC > 0.80). For asymptomatic people the SEM was at most 3 degrees and MDC was 8 degrees with a strong correlation between the dominant and nondominant sides (r > 0.72). The mean absolute values and lower bound scores were at most 10.2 degrees and 26.0 degrees , respectively. These results indicate that this new and novel method of measuring HBB ROM is accurate, has good inter- and intra rater reliability, and provides normal values for between-limb ROM variability. PMID- 27618123 TI - Revisiting the Corticomotor Plasticity in Low Back Pain: Challenges and Perspectives. AB - Chronic low back pain (CLBP) is a recurrent debilitating condition that costs billions to society. Refractoriness to conventional treatment, lack of improvement, and associated movement disorders could be related to the extensive brain plasticity present in this condition, especially in the sensorimotor cortices. This narrative review on corticomotor plasticity in CLBP will try to delineate how interventions such as training and neuromodulation can improve the condition. The review recommends subgrouping classification in CLBP owing to brain plasticity markers with a view of better understanding and treating this complex condition. PMID- 27618127 TI - Stereoselective Domino Carbocyclizations of gamma- and delta-Cyano-N tosylhydrazones with Alkenylboronic Acids with Formation of Two Different C(sp(3))-C(sp(2)) Bonds on a Quaternary Stereocenter. AB - A novel strategy for the synthesis of functionalized carbocycles is defined, through the cascade carbocyclization of alkenylboronic acids with delta- or gamma cyano-N-tosylhydrazones. In the reaction, two C(sp(3))-C(sp(2)) bonds are formed on the former hydrazonic carbon generating an all-carbon quaternary stereocenter, and leading to cyclic ketones featuring an alkenyl side chain with complete diastereoselectivity. The processes are conducted under very simple experimental conditions, only in the presence of K2CO3, in 1,4-dioxane as solvent and under microwave irradiation, and have been applied for the synthesis of a wide structural variety of fused cyclopentanones and cyclohexanones. Moreover, the versatility of this methodology has been demonstrated in the structural modification of androsterone. PMID- 27618125 TI - Altered membrane properties and firing patterns of external globus pallidus neurons in the R6/2 mouse model of Huntington's disease. AB - In mouse models of Huntington's disease (HD), striatal neuron properties are significantly altered. These alterations predict changes in striatal output regions. However, little is known about alterations in those regions. The present study examines changes in passive and active membrane properties of neurons in the external globus pallidus (GPe), the first relay station of the indirect pathway, in the R6/2 mouse model of juvenile HD at presymptomatic (1 month) and symptomatic (2 month) stages. In GPe, two principal types of neurons can be distinguished based on firing properties and the presence (type A) or absence (type B) of Ih currents. In symptomatic animals (2 month), cell membrane capacitance and input resistance of type A neurons were increased compared with controls. In addition, action potential afterhyperpolarization amplitude was reduced. Although the spontaneous firing rate of GPe neurons was not different between control and R6/2 mice, the number of spikes evoked by depolarizing current pulses was significantly reduced in symptomatic R6/2 animals. In addition, these changes were accompanied by altered firing patterns evidenced by increased interspike interval variation and increased number of bursts. Blockade of GABAA receptors facilitated bursting activity in R6/2 mice but not in control littermates. Thus, alterations in firing patterns could be caused by changes in intrinsic membrane conductances and modulated by synaptic inputs. (c) 2016 Wiley Periodicals, Inc. PMID- 27618128 TI - Pharmaceuticals Licensing and Reimbursement in the European Union, United States, and Japan. AB - This article describes recent developments in licensing and reimbursement policies in the EU, US, and Japan, examines causes of changes and compares differences and projects trends. With respect to licensing, the European Medicines Agency (EMA), US Food and Drug Administration (FDA), and Japan's Pharmaceuticals and Medical Devices Agency (PMDA) are committed to rigorous evaluation of pharmaceuticals in advance of market access with feedback from postmarket experience. The EMA is exploring integrated adaptive pathways for licensing, with formal pilot tests to provide a practical proof of concept. The FDA is augmenting traditional licensing procedures through reforms including Breakthrough Product Designation. The PMDA is implementing reforms to foster innovation and earlier patient access through its Sakigake strategy and licensing reforms on regenerative medicines. With respect to reimbursement, several generalizations emerge. Relative to US counterparts, EU payers typically set higher standards for evidence of effectiveness as a condition of reimbursement, impose tougher limits on reimbursement by indication, and drive harder deals in negotiations over prices. PMID- 27618129 TI - Mixtures, Metabolites, and Mechanisms: Understanding Toxicology Using Zebrafish. AB - For more than 60 years, zebrafish have been used in toxicological studies. Due to their transparency, genetic tractability, and compatibility with high-throughput screens, zebrafish embryos are uniquely suited to study the effects of pharmaceuticals and environmental insults on embryonic development, organ formation and function, and reproductive success. This special issue of Zebrafish highlights the ways zebrafish are used to investigate the toxic effects of endocrine disruptors, pesticides, and heavy metals. PMID- 27618130 TI - Histological and Transcriptomic Changes in Male Zebrafish Testes Due to Early Life Exposure to Low Level 2,3,7,8-Tetrachlorodibenzo-p-Dioxin. AB - We have shown that zebrafish (Danio rerio) are an excellent model for evaluating the link between early life stage exposure to environmental chemicals and disease in adulthood and subsequent unexposed generations. Previously, we used this model to identify transgenerational effects of dioxin (2,3,7,8-tetrachlorodibenzo-p dioxin [TCDD]) on skeletal development, sex ratio, and reproductive capacity. Transgenerational inheritance of TCDD toxicity, notably decreased reproductive capacity, appears to be mediated through the male germ line. Thus, we examine testicular tissue for structural and gene expression changes using histology, microarray, and quantitative reverse transcription polymerase chain reaction (qRT PCR). Histological analysis revealed decreased spermatozoa with concurrent increase in spermatogonia, and decreased germinal epithelium thickness in TCDD exposed males compared with controls. We also identified altered expression of genes associated with testis development, steroidogenesis, spermatogenesis, hormone metabolism, and xenobiotic response. Altered genes are in pathways involving lipid metabolism, molecular transport, small molecule biochemistry, cell morphology, and metabolism of vitamins and minerals. These data will inform future investigations to elucidate the mechanism of adult-onset and transgenerational infertility due to TCDD exposure in zebrafish. PMID- 27618133 TI - Odd-parity currents induced by dynamic deformations in graphene-like systems. AB - Reduced (3 + 1)-dimensional Dirac systems with inter-pseudo-spin and inter valley scattering are employed to investigate current responses to (chiral) gauge fields in graphene-like systems. From (chiral) current-(chiral) current correlation functions, we derive the current responses. Except for electric currents induced by external gauge fields, we find the inter-valley scattering can break the topological nature of odd-parity currents. Given the proper conditions, this property can help us realize valley-polarized electric currents. Through the dynamic deformations generating the chiral gauge fields, we find the vortex-like currents while their profiles can be tuned by superposition of some deformations. In particular, we find a more manageable approach to realize the topological electric current by choosing a linear dynamic deformation. PMID- 27618134 TI - Is negative multiparametric magnetic resonance imaging really able to exclude significant prostate cancer? The real-life experience. AB - OBJECTIVES: To evaluate the histopathological results after radical prostatectomy (RP) in patients that had normal preoperative multiparametric magnetic resonance imaging (mpMRI), in order to determine whether they had significant or insignificant disease. Moreover, we evaluated the influence of the expertise of the radiologist on the results. PATIENTS AND METHODS: We retrospectively included patients who underwent RP in our centre and who had a preoperative negative mpMRI. The MRIs were considered negative when no suspicious lesion was seen or when the Prostate Imaging Reporting and Data System version 1 score was <7. We used Pathological tumour-node-metastasis staging and Gleason score on pathology reports, and whole-mount sections to calculate tumour volume. RESULTS: We identified 101 patients from 2009 to 2015. Final pathology showed that 16.9% had extraprostatic extension, 13.8% had primary Gleason pattern 4 (4 + 3 and above), 47.5% had secondary Gleason pattern 4 or 5, and 55.9% and 20.6% had a main tumour volume of >=0.5 and >=2 mL, respectively. When limiting the analysis to expert reading only, the numbers improved: only one patient (3.4%) had extraprostatic extension (P < 0.05), one patient (3.4%) had primary Gleason pattern 4 (P = 0.05), and 64.7% and 5.9% had a main tumour volume of >=0.5 and >=2 mL, respectively (P = 0.01). CONCLUSION: A negative MRI does not guarantee the absence of significant prostate cancer. PMID- 27618135 TI - Novel mutation in TCAP manifesting with asymmetric calves and early-onset joint retractions. AB - A 29-year-old man, born from consanguineous parents, started with toe walking and frequent falls during his second year of life. He developed weakness in lower limbs during the first decade that subsequently extended to upper limbs. On examination, the patient had weakness in proximal muscles of all four limbs and in the tibialis anterior muscle. In addition, he had bilateral Achilles and patellar contractures, bilateral scapular winging, asymmetric calves and a positive Beevor sign, an upward movement of the umbilicus on contraction of rectus femoris due to weakness in the lower part. The muscle biopsy showed dystrophic changes and lobulated fibers. Genetic analysis through a next generation sequencing panel of genes related to neuromuscular disorders revealed a novel homozygous nonsense mutation (p.Tyr85*) in the TCAP gene. Subsequent western blot assay showed a complete telethonin deficiency. Our observation expands the phenotypic spectrum of TCAP mutations and indicates that telethonin deficiency should be considered in the differential diagnosis of patients presenting with asymmetric calves and early joint retractions. PMID- 27618136 TI - Mitochondrial dysfunction in myofibrillar myopathy. AB - Myofibrillar myopathies (MFM) are characterised by focal myofibrillar destruction and accumulation of myofibrillar elements as protein aggregates. They are caused by mutations in the DES, MYOT, CRYAB, FLNC, BAG3, DNAJB6 and ZASP genes as well as other as yet unidentified genes. Previous studies have reported changes in mitochondrial morphology and cellular positioning, as well as clonally-expanded, large-scale mitochondrial DNA (mtDNA) deletions and focal respiratory chain deficiency in muscle of MFM patients. Here we examine skeletal muscle from patients with desmin (n = 6), ZASP (n = 1) and myotilin (n = 2) mutations and MFM protein aggregates, to understand how mitochondrial dysfunction may contribute to the underlying mechanisms causing disease pathology. We have used a validated quantitative immunofluorescent assay to study respiratory chain protein levels, together with oxidative enzyme histochemistry and single cell mitochondrial DNA analysis, to examine mitochondrial changes. Results demonstrate a small number of clonally-expanded mitochondrial DNA deletions, which we conclude are due to both ageing and disease pathology. Further to this we report higher levels of respiratory chain complex I and IV deficiency compared to age matched controls, although overall levels of respiratory deficient muscle fibres in patient biopsies are low. More strikingly, a significantly higher percentage of myofibrillar myopathy patient muscle fibres have a low mitochondrial mass compared to controls. We concluded this is mechanistically unrelated to desmin and myotilin protein aggregates; however, correlation between mitochondrial mass and muscle fibre area is found. We suggest this may be due to reduced mitochondrial biogenesis in combination with muscle fibre hypertrophy. PMID- 27618137 TI - Clinical features of the pathogenic m.5540G>A mitochondrial transfer RNA tryptophan gene mutation. AB - Mitochondrial DNA disease is one of the most common groups of inherited neuromuscular disorders and frequently associated with marked phenotypic and genotypic heterogeneity. We describe an adult patient who initially presented with childhood-onset ataxia without a family history and an unremarkable diagnostic muscle biopsy. Subsequent multi-system manifestations included basal ganglia calcification, proteinuria, cataract and retinitis pigmentosa, prompting a repeat muscle biopsy that showed features consistent with mitochondrial myopathy 13 years later. She had a stroke with restricted diffusion change in the basal ganglia and internal capsule at age 44 years. Molecular genetic testing identified a previously-reported pathogenic, heteroplasmic mutation in the mitochondrial-encoded transfer RNA tryptophan (MT-TW) gene which based on family studies was likely to have arisen de novo in our patient. Interestingly, we documented an increase in the mutant mtDNA heteroplasmy level in her second biopsy (72% compared to 56%), reflecting the progression of clinical disease. PMID- 27618139 TI - Significant Decrease in Plasma Levels of D-Dimer, Interleukin-8, and Interleukin 12 After a 12-Month Treatment with Rosuvastatin in HIV-Infected Patients Under Antiretroviral Therapy. AB - OBJECTIVES: Statins have shown anti-inflammatory and immune-modulatory properties in both general and HIV-infected population, but their effect on plasma D-dimer levels is controversial and it has not been investigated to date in HIV-positive patients. The aim of our study was to assess the effect of rosuvastatin on D dimer and other serum inflammation markers among these subjects. METHODS: Prospective, cohort study of HIV-1-infected adult patients receiving a stable combination antiretroviral therapy (cART), who started a lipid-lowering therapy with rosuvastatin (10 mg daily) and were followed up for at least 12 months. The primary endpoint was the change at month 12 in the median plasma concentration of D-dimer. The secondary endpoints included the variation in median plasma levels of these inflammatory biomarkers: interleukin-8 (IL-8), interleukin-10 (IL-10), and interleukin-12 (IL-12). RESULTS: Sixty-two patients were enrolled in the study, and the endpoints were available for 54 subjects. After 12 months, a significant decrease in median plasma concentration of D-dimer was observed ( 21.4%; interquartile range [IQR], -35.5; -4.2; p = .029). With regard to the inflammatory biomarkers, a significant decrease in median levels of IL-8 (-24.6%; IQR, -30.8; -1.8; p = .012) and IL-12 (-18.7%; IQR, -25.8; +2.5; p = .033) was also observed. Rosuvastatin led to a significant reduction in serum lipid values and showed a good tolerability profile. CONCLUSIONS: Our findings show that a 12 month treatment with rosuvastatin associated with an effective cART can significantly decrease the plasma levels of D-dimer, IL-8, and IL-12, and suggest a potential role for this statin to reduce activated coagulation and systemic inflammation among HIV-infected persons. PMID- 27618140 TI - Acute Optogenetic Modulation of Cardiac Twitch Dynamics Explored Through Modeling. AB - Optogenetic approaches allow cellular membrane potentials to be perturbed by light. When applied to muscle cells, mechanical events can be controlled through a process that could be termed "optomechanics." Besides functioning as an optical on/off switch, we hypothesized that optomechanical control could include the ability to manipulate the strength and duration of contraction events. To explore this possibility, we constructed an electromechanical model of the human ventricular cardiomyocyte while adding a representation of channelrhodopsin-2 (ChR2), a light-activated channel commonly used in optogenetics. Two hybrid stimulus protocols were developed that combined light-based stimuli with traditional electrical current (all-or-none) excitation. The first protocol involved delivery of a subthreshold optical stimulus followed 50-90 ms later by an electrical stimulus. The result was a graded inhibition of peak cellular twitch force in concert with a prolongation of the intracellular Ca2+ transient. The second protocol was comprised of an electrical stimulus followed by a long light pulse (250-350 ms) that acted to prolong the cardiac action potential (AP). This created a pulse duration-dependent prolongation of the intracellular Ca2+ transient that in turn altered the rate of muscle relaxation without changing peak twitch force. These results illustrate the feasibility of acute, optomechanical manipulation of cardiomyocyte contraction and suggest that this approach could be used to probe the dynamic behavior of the cardiac sarcomere without altering its intrinsic properties. Other experimentally meaningful stimulus protocols could be designed by making use of the optomechanical cardiomyocyte model presented here. PMID- 27618141 TI - Rule induction performance in amnestic mild cognitive impairment and Alzheimer's dementia: examining the role of simple and biconditional rule learning processes. AB - INTRODUCTION: Rule induction tests such as the Wisconsin Card Sorting Test require executive control processes, but also the learning and memorization of simple stimulus-response rules. In this study, we examined the contribution of diminished learning and memorization of simple rules to complex rule induction test performance in patients with amnestic mild cognitive impairment (aMCI) or Alzheimer's dementia (AD). METHOD: Twenty-six aMCI patients, 39 AD patients, and 32 control participants were included. A task was used in which the memory load and the complexity of the rules were independently manipulated. This task consisted of three conditions: a simple two-rule learning condition (Condition 1), a simple four-rule learning condition (inducing an increase in memory load, Condition 2), and a complex biconditional four-rule learning condition-inducing an increase in complexity and, hence, executive control load (Condition 3). RESULTS: Performance of AD patients declined disproportionately when the number of simple rules that had to be memorized increased (from Condition 1 to 2). An additional increment in complexity (from Condition 2 to 3) did not, however, disproportionately affect performance of the patients. Performance of the aMCI patients did not differ from that of the control participants. In the patient group, correlation analysis showed that memory performance correlated with Condition 1 performance, whereas executive task performance correlated with Condition 2 performance. CONCLUSIONS: These results indicate that the reduced learning and memorization of underlying task rules explains a significant part of the diminished complex rule induction performance commonly reported in AD, although results from the correlation analysis suggest involvement of executive control functions as well. Taken together, these findings suggest that care is needed when interpreting rule induction task performance in terms of executive function deficits in these patients. PMID- 27618143 TI - Trichloroethylene-Induced DNA Methylation Changes in Male F344 Rat Liver. AB - Trichloroethylene (TCE), a common environmental contaminant, causes hepatocellular carcinoma in mice but not in rats. To understand the mechanisms of the species-specific hepatocarcinogenecity of TCE, we examined the methylation status of DNA in the liver of rats exposed to TCE at 0 or 1000 mg/kg b.w. for 5 days using MeDIP-chip, bisulfite sequencing, COBRA, and LC-MS/MS. The related mRNA expression levels were measured by qPCR. Although no global DNA methylation change was detected, 806 genes were hypermethylated and 186 genes were hypomethylated. The genes with hypermethylated DNA were enriched in endocytosis, MAPK, and cAMP signaling pathways. We further confirmed the hypermethylation of Uhrf2 DNA and the hypomethylation of Hadhb DNA, which were negatively correlated with their mRNA expression levels. The transcriptional levels of Jun, Ihh, and Tet2 were significantly downregulated, whereas Cdkn1a was overexpressed. No mRNA expression change was found for Mki67, Myc, Uhrf1, and Dnmt1. In conclusion, TCE induced DNA methylation changes in rats appear to suppress instead of promote hepatocarcinogenesis, which might play a role in the species-specific hepatocarcinogenecity of TCE. PMID- 27618142 TI - Equity and practice issues in colorectal cancer screening: Mixed-methods study. AB - OBJECTIVE: To investigate overall colorectal cancer (CRC) screening rates, patterns in the use of types of CRC screening, and sociodemographic characteristics associated with CRC screening; and to gain insight into physicians' perceptions about and use of fecal occult blood testing [FOBT] and colonoscopy for patients at average risk of CRC. DESIGN: Mixed-methods study using cross-sectional administrative data on patient sociodemographic characteristics and semistructured telephone interviews with physicians. SETTING: Toronto, Ont. PARTICIPANTS: Patients aged 50 to 74 years and physicians in family health teams in the Toronto Central Local Health Integration Network. MAIN OUTCOME MEASURES: Rates of CRC screening by type; sociodemographic characteristics associated with CRC screening; thematic analysis using constant comparative method for semistructured interviews. MAIN FINDINGS: Ontario administrative data on CRC screening showed lower overall screening rates among those who were younger, male patients, those who had lower income, and recent immigrants. Colonoscopy rates were especially low among those with lower income and those who were recent immigrants. Semistructured interviews revealed that physician opinions about CRC screening for average-risk patients were divided: one group of physicians accepted the evidence and recommendations for FOBT and the other group of physicians strongly supported colonoscopy for these patients, believing that the FOBT was an inferior screening method. Physicians identified specialist recommendations and patient expectations as factors that influenced their decisions regarding CRC screening type. CONCLUSION: There was considerable variation in CRC screening by sociodemographic characteristics. A key theme that emerged from the interviews was that physicians were divided in their preference for FOBT or colonoscopy; factors that influenced physician preference included the health care system, recommendations by other specialists, and patient characteristics. Providing an informed choice of screening method to patients might result in higher screening rates and fewer disparities. Changes in policy and physician attitudes might be needed in order for this to occur. PMID- 27618144 TI - Ponatinib Induces a Persistent Molecular Response and Graft-versus-Host Disease/Graft-versus-Leukemia Effect in a Patient with Philadelphia-Positive Acute Lymphoblastic Leukemia with a T315I Mutation following Early Relapse after Allogeneic Transplant. AB - We describe the case of a patient with a Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) treated with dasatinib plus steroids as the first line therapy who achieved a molecular complete remission and then underwent a matched, unrelated donor allogeneic transplant. Five months after the transplant, he experienced a disease relapse with an T315I mutation, which was resistant to salvage chemotherapy. Once the details of the T315I mutation were acquired, we initiated ponatinib treatment at a standard dosage and observed a rapid decrease of minimal residual disease (MRD) at molecular assessment. The bone marrow evaluation after 2, 3, 6, 10 and 13 months was negative for MRD. After starting ponatinib, the patient experienced a skin graft-versus-host disease (GVHD), whereas no occurrence of GVHD was observed after transplant, suggesting that the efficacy of ponatinib could be related not only to the direct antileukemic effect, but also to its ability to promote an indirect graft-versus-leukemia effect. Ponatinib was well tolerated but a thyroid dysfunction mimicking a cardiovascular toxicity was observed and solved with hormonal substitutive treatment. PMID- 27618145 TI - Objective Measure of Nasal Air Emission Using Nasal Accelerometry. AB - Purpose: This article describes the development and initial validation of an objective measure of nasal air emission (NAE) using nasal accelerometry. Method: Nasal acceleration and nasal airflow signals were simultaneously recorded while an expert speech language pathologist modeled NAEs at a variety of severity levels. In addition, microphone and nasal accelerometer signals were collected during the production of /palphapalphapalphapalpha/ speech utterances by 25 children with and without cleft palate. Fourteen inexperienced raters listened to the microphone signals from the pediatric speakers and rated the samples for the severity of NAE using direct magnitude estimation. Mean listener ratings were compared to a novel quantitative measurement of NAE derived from the nasal acceleration signals. Results: Correlation between the nasal acceleration energy measure and the measured nasal airflow was high (r = .87). Correlation between the measure and auditory-perceptual ratings was moderate (r = .49). Conclusion: The measure presented here is quantitative and noninvasive, and the required hardware is inexpensive ($150). Future studies will include speakers with a wider range of NAE severity and etiology, including cleft palate, hearing impairment, or dysarthria. Further development will also involve validation of the measure against airflow measures across subjects. PMID- 27618146 TI - Development, Evaluation, and Comparison of Land Use Regression Modeling Methods to Estimate Residential Exposure to Nitrogen Dioxide in a Cohort Study. AB - We used a network of 135 NO2 passive diffusion tube sites to develop land use regression (LUR) models in a UK conurbation. Network sites were divided into four groups (32-35 sites per group) and models developed using combinations of 1-3 groups of "training" sites to evaluate how the number of training sites influenced model performance and residential NO2 exposure estimates for a cohort of 13 679 participants. All models explained moderate to high variance in training and independent "hold-out" data (Training adj. R2: 62-89%; Hold-out R2: 44-85%). Average hold-out R2 increased by 9.5%, while average training adj. R2 decreased by 7.2% when the number of training groups was increased from 1 to 3. Exposure estimate precision improved with increasing number of training sites (median intralocation relative standard deviations of 19.2, 10.3, and 7.7% for 1 group, 2-group and 3-group models respectively). Independent 1-group models gave highly variable exposure estimates suggesting that variations in LUR sampling networks with relatively low numbers of sites (<=35) may substantially alter exposure estimates. Collectively, our analyses suggest that use of more than 60 training sites has quantifiable benefits in epidemiological application of LUR models. PMID- 27618149 TI - Dietary Associations with a Breast Cancer Risk Biomarker Depend on Menopause Status. AB - We investigated how timing influences the role of diet in breast cancer risk with a cross-sectional study of pre-malignant change in breast tissue. Women with an elevated risk of developing breast cancer (33 premenopausal and 32 postmenopausal) completed the National Cancer Institute's food frequency questionnaire and underwent random periareolar fine-needle aspiration for evaluation of cytologic atypia, an established risk biomarker. Fatty acid composition of breast adipose was measured in 32 (49%) subjects. We found that premenopausal and postmenopausal women had similar diets, but the associations between atypia and intake of total n-3 polyunsaturated fatty acids (PUFA) and soy differed by menopause status (both P interaction < 0.001). Total n-3 PUFA intake was inversely associated with atypia among premenopausal women (P < 0.0001), but not among postmenopausal women (P = 0.91); associations were similar for soy (P = 0.0003 and P = 0.48, respectively). This pattern of dietary interaction with menopause was mirrored in tissue fatty acids (P interaction < 0.05), wherein 1) higher levels of linolelaidic acid (an industrially-produced trans fat) and 2) lower levels of docosahexaenoic acid (the predominant long-chain n-3 PUFA) in breast adipose were associated with atypia in premenopausal (both P < 0.05) but not postmenopausal women (both P > 0.37). Dietary associations with breast cancer risk are stronger prior to menopause. PMID- 27618147 TI - Substrate specificity characterization for eight putative nudix hydrolases. Evaluation of criteria for substrate identification within the Nudix family. AB - The nearly 50,000 known Nudix proteins have a diverse array of functions, of which the most extensively studied is the catalyzed hydrolysis of aberrant nucleotide triphosphates. The functions of 171 Nudix proteins have been characterized to some degree, although physiological relevance of the assayed activities has not always been conclusively demonstrated. We investigated substrate specificity for eight structurally characterized Nudix proteins, whose functions were unknown. These proteins were screened for hydrolase activity against a 74-compound library of known Nudix enzyme substrates. We found substrates for four enzymes with kcat /Km values >10,000 M-1 s-1 : Q92EH0_LISIN of Listeria innocua serovar 6a against ADP-ribose, Q5LBB1_BACFN of Bacillus fragilis against 5-Me-CTP, and Q0TTC5_CLOP1 and Q0TS82_CLOP1 of Clostridium perfringens against 8-oxo-dATP and 3'-dGTP, respectively. To ascertain whether these identified substrates were physiologically relevant, we surveyed all reported Nudix hydrolytic activities against NTPs. Twenty-two Nudix enzymes are reported to have activity against canonical NTPs. With a single exception, we find that the reported kcat /Km values exhibited against these canonical substrates are well under 105 M-1 s-1 . By contrast, several Nudix enzymes show much larger kcat /Km values (in the range of 105 to >107 M-1 s-1 ) against noncanonical NTPs. We therefore conclude that hydrolytic activities exhibited by these enzymes against canonical NTPs are not likely their physiological function, but rather the result of unavoidable collateral damage occasioned by the enzymes' inability to distinguish completely between similar substrate structures. Proteins 2016; 84:1810-1822. (c) 2016 Wiley Periodicals, Inc. PMID- 27618148 TI - Effects of Serum Triglycerides on Prostate Cancer and Breast Cancer Risk: A Meta Analysis of Prospective Studies. AB - Epidemiological studies show conflicting results regarding the link between serum triglyceride and the risk of prostate cancer and breast cancer. Therefore, we performed a meta-analysis of prospective studies to clarify this association. We searched PubMed, EMBASE, the Chinese Biomedical Database (CBM), and the China National Knowledge Infrastructure (CNKI) database to identify relevant prospective studies of the relationship between serum triglyceride and prostate cancer and breast cancer risk. Study-specific estimates adjusting for potential confounders were combined to evaluate a summary relative risks (RRs) and 95% confidence intervals (95% CIs) using a fixed- or random-effects model. A total of 11 prospective studies (619,410 subjects and 15,691 incident prostate cancer patients) and 8 prospective studies (590,878 subjects and 12,177 incident breast cancer patients) were respectively included in our meta-analysis to assess the associations of serum triglyceride with prostate cancer and breast cancer risk. The pooled adjusted RR estimates for prostate cancer and breast cancer for the highest versus the lowest exposure levels of serum triglycerides were 0.95 (95% CI: 0.87-1.04) and 0.94 (95% CI: 0.87-1.00), respectively. Additionally, a dose response analysis revealed that serum levels of triglycerides were not associated with the risk of prostate cancer and breast cancer. We found that serum triglyceride was not related to the risk of prostate cancer and breast cancer. PMID- 27618151 TI - Sporoderm-Broken Spores of Ganoderma lucidum Inhibit the Growth of Lung Cancer: Involvement of the Akt/mTOR Signaling Pathway. AB - The sporoderm-broken spores of Ganoderma lucidum (SBGS) and their extracts exhibited a wide range of biological activities. In the present study, we prepare ethanol/ethanol extract (E/E-SBGS) and ethanol/aqueous extract (E/A-SBGS) from SBGS and examine their antitumor activities against human lung cancer. Our results showed that E/E-SBGS, not E/A-SBGS, inhibited the survival and migration of lung cancer cells in a dose-dependent manner. E/E-SBGS arrested cell cycle at G2/M phase and triggered apoptosis by decreasing the expression and activity of cell cycle regulators, cyclin B1 and cdc2, as well as anti-apoptotic proteins, Bcl-2 and Bcl-xl. Consequently, colony formation of lung cancer cells was markedly blocked by E/E-SBGS at subtoxic concentrations. Oral administration of both E/E-SBGS and SBGS significantly suppressed tumor volume and tumor weight without gross toxicity in mice. Mechanism study showed that E/E-SBGS dose dependently suppressed the activation of Akt, the mammalian target of rapamycin (mTOR) and their downstream molecules S6 kinase and 4E-BP1 in treated tumor cells. Taken together, these results indicate that the ethanol extract of sporoderm-broken spores of G. lucidum suppresses the growth of human lung cancer, at least in part, through inhibition of the Akt/mTOR signaling pathway, suggesting its potential role in cancer treatments. PMID- 27618150 TI - A Phenolic Extract Obtained from Methyl Jasmonate-Treated Strawberries Enhances Apoptosis in a Human Cervical Cancer Cell Line. AB - In the present study, we evaluated the effect of methyl jasmonate (MeJA) treatment on strawberry phenolic composition. Strawberry extracts contain a mixture of phenolic compounds possessing several biological properties. We demonstrated that these extracts were more effective in inducing apoptosis in HeLa cells compared to phenolic preparations derived from untreated strawberries. Treatment of strawberries with 0.5% MeJA resulted in increased polyphenols content (from 7.4 to 8.6 mM quercetin equivalents) and antioxidant properties (from 3.9 to 4.6 mM quercetin equivalents). The identification and quantification of phenolic compounds by liquid chromatography-mass spectrometry in the strawberry extracts showed that cyanidin glucoside, pelargonidin glucoside, and ellagic glucoside acid were significantly higher in strawberries treated with MeJA. Phenolic extracts from MeJA-treated strawberries significantly decreased the cell viability in HeLa cells, compared to extracts derived from untreated fruits. We hypothesized that the enhanced apoptotic activity of MeJA-treated strawberries was due to a synergistic or additive effect of different phenolic compounds present in the extract, rather than the activity of a single molecule. PMID- 27618152 TI - Antitumoral Effect of Hibiscus sabdariffa on Human Squamous Cell Carcinoma and Multiple Myeloma Cells. AB - Cancer is a leading cause of death worldwide. Despite therapeutic improvements, some cancers are still untreatable. Recently there has been an increasing interest in the use of natural substances for cancer prevention and treatment. Hibiscus sabdariffa (HS) is a plant, belonging to Malvaceae family, widespread in South Asia and Central Africa. HS extract (HSE) used in folk medicine, gained researchers' interest thanks to its antioxidant, anti-inflammatory, and chemopreventive properties. In the present study, we initially assessed HSE effect on a panel of human tumor cell lines. Then we focused our study on the following that are most sensitive to HSE action cell lines: Multiple Myeloma (MM) cells (RPMI 8226) and Oral Squamous Cell Carcinoma (OSCC) cells (SCC-25). In both RPMI 8226 and SCC-25 cells, HSE impaired cell growth, exerted a reversible cytostatic effect, and reduced cell motility and invasiveness. We evaluated the involvement of MAPKs ERK1/2 and p38 in HSE effects by using specific inhibitors, U0126 and SB203580, respectively. For both SCC-25 and RPMI 8226, HSE cytostatic effect depends on p38 activation, whereas ERK1/2 modulation is crucial for cell motility and invasiveness. Our results suggest that HSE may be a potential therapeutic agent against MM and OSCC. PMID- 27618153 TI - Emu Oil Combined with LyprinolTM Reduces Small Intestinal Damage in a Rat Model of Chemotherapy-Induced Mucositis. AB - Chemotherapy-induced mucositis is characterized by inflammation and ulcerating lesions lining the alimentary tract. Emu Oil and LyprinolTM have independently demonstrated their therapeutic potential in intestinal inflammatory disorders, including mucositis. We investigated Emu Oil and LyprinolTM in combination for their further potential to alleviate chemotherapy-induced mucositis in rats. Rats were gavaged with (1 ml) water, Olive Oil, Emu Oil + Olive Oil, LyprinolTM + Olive Oil or Emu Oil + LyprinolTM from Days 0 to 7, injected with saline (control) or 5-Fluorouracil (5-FU) on Day 5 and euthanized on Day 8. Myeloperoxidase (MPO) activity (indicative of acute inflammation), histological severity scores, and intestinal architecture were quantified. Myeloperoxidase activity was significantly increased in the jejunum and ileum following 5-FU, compared to saline controls. Both Olive Oil and Emu Oil + LyprinolTM significantly reduced jejunal MPO levels (1.8-fold and 1.7-fold, respectively), whereas only Emu Oil + LyprinolTM significantly decreased ileal MPO levels, relative to 5-FU controls. All oil treatments decreased histological severity scores in the jejunum and ileum, and normalized crypt depth in the mid small intestine, relative to 5-FU controls. Emu Oil combined with LyprinolTM partially reduced acute small intestinal inflammation. Isolating bioactive constituents of these naturally sourced oils could provide a more targeted strategy to protect against intestinal mucositis. PMID- 27618155 TI - Primary Total Hip Arthroplasty With Fourth-Generation Ceramic-on-Ceramic: Analysis of Complications in 939 Consecutive Cases Followed for 2-10 Years. AB - BACKGROUND: Delta ceramics may be the bearing of choice for younger and active patients due to its improved toughness and wear characteristics, provided there is no risk of fracture. However, ceramic fracture is the most serious complication related to this type of bearing. Although millions of Delta ceramics have been implanted worldwide, short to midterm results have been scarcely reported in the literature. The purpose of this study was to report the complication rate at short to midterm follow-up associated with the bearing surface used in a series of primary total hip arthroplasties with Delta ceramic on-ceramic bearings performed in a single institution. METHODS: A total of 939 cases (880 patients) undergoing primary total hip arthroplasty with fourth generation Delta ceramic-on-ceramic bearings were retrospectively reviewed. They were followed for an average of 5.3 years (2-10 years). RESULTS: One hip experienced a liner fracture, 2 cups presented early loosening due to friction between the acetabular screw and the backside of the liner, one femoral ball head had a fracture; one case of squeaking was reported, which is impending revision. Considering revision or impending revision in relationship with the bearing surface as the end point, the mean survival rate was 99.3% (confidence interval 95%, 98.3%-99.7%) at 2-10 years. CONCLUSION: This study showed a low rate of ceramic fracture compared with others; however, it was much higher than the complication rate presented by the manufacturers. The complications observed were directly related to technical errors that surgeons should avoid when using this type of surface. PMID- 27618154 TI - Bioassay-Guided Fractionation and In Vitro Antiproliferative Effects of Fractions of Artemisia nilagirica on THP-1 cell line. AB - ABSTACT Artemisia nilagirica (Clarke) is a widely used medicinal herb in Indian traditional system of medicine. Therefore, the present study was designed to evaluate the effects of A. nilagirica extracts/fractions on inhibition of proliferation and apoptosis in a human monocytic leukemia (THP-1) cell line. The crude extracts (A. nilagirica ethyl acetate extract [ANE] and A. nilagirica methanolic extract [ANA]) showed cytotoxic activity toward THP-1 cells with the IC50 values of 38.21 +/- 7.37 and 132.41 +/- 7.19 ug/ml, respectively. However, the cytotoxic activity of active fractions (ANE-B and ANM-9) obtained after column chromatography was found to be much more pronounced than their parent extracts. The IC50 values of ANE-B and ANM-9 were found to be 27.04 +/- 2.54 ug/ml and 12.70 +/- 4.79 ug/ml, respectively, suggesting greater susceptibility of the malignant cells. Cell cycle analysis and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end-labeling (TUNEL) assay revealed that inhibition of cell growth by A. nilagirica fractions on THP-1 cells was mediated by apoptosis. Active fractions of A. nilagirica increased the expression levels of caspase-3, -7, and poly-ADP-ribose polymerase (PARP), a critical member of the apoptotic pathway. These results suggested that active fractions of A. nilagirica may play a promising role in growth suppression by inducing apoptosis in human monocytic leukemic cells via mitochondria-dependent and death receptor-dependent apoptotic pathways. PMID- 27618156 TI - Are Chronic Periodontitis and Gingivitis Associated with Dementia? A Nationwide, Retrospective, Matched-Cohort Study in Taiwan. AB - BACKGROUND: Chronic periodontitis and gingivitis are associated with various diseases; however, their impact on dementia is yet to be elucidated. This study is aimed at investigating the association between chronic periodontitis and gingivitis, and the risk of developing dementia. METHODS: A total of 2,207 patients, with newly diagnosed chronic periodontitis and gingivitis between January 1, 2000 and December 31, 2000, were selected from the National Health Insurance Research Database of Taiwan, along with 6,621 controls matched for sex and age. After adjusting for confounding factors, Cox proportional hazards analysis was used to compare the risk of developing dementia during the 10-year follow-up period. RESULTS: Of the study subjects, 25 (1.13%) developed dementia compared to 61 (0.92%) in the control group. Cox proportional hazards regression analysis revealed that the study subjects were more likely to develop dementia (hazard ratio (HR) 2.085, 95% CI 1.552-4.156, p < 0.001). After adjusting for sex, age, monthly income, urbanization level, geographic region, and comorbidities, the HR for dementia was 2.54 (95% CI 1.297-3.352, p = 0.002). CONCLUSIONS: Patients with chronic periodontitis and gingivitis have a higher risk of developing dementia. However, further studies on other large or national data sets are required to support the current findings. PMID- 27618157 TI - Immobilization of Lipase from Pseudomonas fluorescens on Porous Polyurea and Its Application in Kinetic Resolution of Racemic 1-Phenylethanol. AB - A porous polyurea (PPU) was prepared through a simple protocol by reacting toluene diisocyanate with water in binary solvent of water-acetone. Its amine group was determined through spectrophotometric absorbance based on its iminization with p-nitrobenzaldehyde amines. PPU was then used as a novel polymer support for enzyme immobilization, through activation by glutaraldehyde followed by immobilization of an enzyme, lipase from Pseudomonas fluorescens (PFL), via covalent bonding with the amine groups of lipase molecules. Influences of glutaraldehyde and enzyme concentration and pH in the process were studied. The results revealed that the activity of the immobilized PFL reached a maximum at GA concentration of 0.17 mol/L and at pH 8. Immobilization rate of 60% or higher for PFL was obtained under optimized condition with an enzyme activity of 283 U/mg. The porous structure of PPU, prior to and after GA activation and PFL immobilization, was characterized. The activity of the immobilized PFL at different temperature and pH and its stability at 40 degrees C as well as its reusability were tested. The immobilized enzyme was finally used as enantioselective catalyst in kinetic resolution of racemic 1-phenylethanol (1 PEOH), and its performance compared with the free PFL. The results demonstrate that the enzyme activity and stability were greatly improved for the immobilized PFL, and highly pure enantiomers from racemic 1-PEOH were effectively achieved using the immobilized PFL. Noticeable deactivation of PFL in the resolution was observed by acetaldehyde in situ formed. In addition, the immobilized PFL was readily recovered from the reaction system for reuse. A total of 73% of the initial activity was retained after 5 repeated reuse cycles. This work provides a novel route to preparation of a polyurea porous material and its enzyme immobilization, leading to a novel type of immobilized enzyme for efficient kinetic resolution of racemic molecules. PMID- 27618158 TI - Differences in Cytokine Production during Aging and Its Relationship with Antimicrobial Peptides Production. AB - Aging is a major health issue due to the increased susceptibility of elderly people to infectious, autoimmune, and cardiovascular diseases. Innate immunity is an important mechanism to avoid primary infections; therefore, decreasing of its activity may lead to development of infections. Antimicrobial peptides (AMPs) are effector molecules of innate immunity that can eliminate microbial invaders. The role that cytokines play in the regulation of these innate immune mechanisms needs to be explored. Serum determinations of Th1, Th2, and Th17 cytokines were performed in order to evaluate their association with AMPs human beta-defensin (HBD)-2 and LL-37 in young adults, elder adults, and elder adults with recurrent infections. Our results showed differences in interleukin (IL)-10 and IL-6 among the different groups. Inverse correlations in serum cytokine levels and HBD-2 production were identified for IL-10, IL-2, IL-4, tumor necrosis factor-alpha, and IL-6. Also inverse correlations were identified for IL-10, IL-4, and cathelicidin (LL-37). Such results could impact the development of immunomodulators that promote AMP production to prevent and/or contain infectious diseases in this population. PMID- 27618159 TI - Simplifying the assessment of human breast cancer by mapping a micro-scale heterogeneity index in optical coherence elastography. AB - Surgical treatment of breast cancer aims to identify and remove all malignant tissue. Intraoperative assessment of tumor margins is, however, not exact; thus, re-excision is frequently needed, or excess normal tissue is removed. Imaging methods applicable intraoperatively could help to reduce re-excision rates whilst minimizing removal of excess healthy tissue. Optical coherence elastography (OCE) has been proposed for use in breast-conserving surgery; however, intraoperative interpretation of complex OCE images may prove challenging. Observations of breast cancer on multiple length scales, by OCE, ultrasound elastography, and atomic force microscopy, have shown an increase in the mechanical heterogeneity of malignant breast tumors compared to normal breast tissue. In this study, a micro-scale mechanical heterogeneity index is introduced and used to form heterogeneity maps from OCE scans of 10 ex vivo human breast tissue samples. Through comparison of OCE, optical coherence tomography images, and corresponding histology, malignant tissue is shown to possess a higher heterogeneity index than benign tissue. The heterogeneity map simplifies the contrast between tumor and normal stroma in breast tissue, facilitating the rapid identification of possible areas of malignancy, which is an important step towards intraoperative margin assessment using OCE. PMID- 27618161 TI - Cryopreservation-Altered Expression of RNA and Protein Markers in Biological Specimens. AB - The preservation of DNA, RNA, and protein markers in biological specimens is essential for initial diagnosis, subsequent verification, and comparison, as well as for archival retention of pathological materials in modern molecular diagnostics and precision medicine. Considerable attention has been paid to the methods of collection, handling, and preparation of specimens for initial testing, but insufficient attention to the long-term specimen preservation for later verification, comparison, and archival retention. In the present study, we have investigated the changes of expressions of RNAs and proteins in Hep-G2 cell specimens after cryopreservation at -80 degrees C and in liquid nitrogen. Storage temperature and different cryoprotective agent (CPA) solutions not only affect cell viability but also more importantly the retention of various molecular markers after storage as detected by western blot and real-time fluorescent quantitative polymerase chain reaction. While the presence of CPAs increased the survival rates of cells after cryopreservation as expected, there was no consistent trend observed with regard to the RNA expression measurements. The data have significant implications with regard to the accuracy and interpretation of acquired data from specimens that have been cryopreserved without RNA and protein stabilization and point to the need for rethinking the assumptions, strategies, and criteria of optimizing biological specimen cryopreservation in molecular diagnostics. PMID- 27618166 TI - Genetic and epigenetic control of transfer cell development in plants. AB - The inter-cellular translocation of nutrients in plant is mediated by highly specialized transfer cells (TCs). TCs share similar functional and structural features across a wide range of plant species, including location at plant exchange surfaces, rich in secondary wall ingrowths, facilitation of nutrient flow, and passage of select molecules. The fate of endosperm TCs is determined in the TC fate acquisition stage (TCF), before the structure features are formed in the TC differentiation stage (TCD). At present, the molecular basis of TC development in plants remains largely unknown. In this review, we summarize the important roles of the signaling molecules in different development phases, such as sugars in TCF and phytohormones in TCD, and discuss the genetic and epigenetic factors, including TC-specific genes and endogenous plant peptides, and their crosstalk with these signaling molecules as a complex regulatory network in regulation of TC development in plants. PMID- 27618162 TI - Kidney Outcomes 5 Years After Pediatric Cardiac Surgery: The TRIBE-AKI Study. AB - Importance: Acute kidney injury (AKI) after pediatric cardiac surgery is associated with high short-term morbidity and mortality; however, the long-term kidney outcomes are unclear. Objective: To assess long-term kidney outcomes after pediatric cardiac surgery and to determine if perioperative AKI is associated with worse long-term kidney outcomes. Design, Setting, and Participants: This prospective multicenter cohort study recruited children between ages 1 month to 18 years who underwent cardiopulmonary bypass for cardiac surgery and survived hospitalization from 3 North American pediatric centers between July 2007 and December 2009. Children were followed up with telephone calls and an in-person visit at 5 years after their surgery. Exposures: Acute kidney injury defined as a postoperative serum creatinine rise from preoperative baseline by 50% or 0.3 mg/dL or more during hospitalization for cardiac surgery. Main Outcomes and Measures: Hypertension (blood pressure >=95th percentile for height, age, sex, or self-reported hypertension), microalbuminuria (urine albumin to creatinine ratio >30 mg/g), and chronic kidney disease (serum creatinine estimated glomerular filtration rate [eGFR] <90 mL/min/1.73 m2 or microalbuminuria). Results: Overall, 131 children (median [interquartile range] age, 7.7 [5.9-9.9] years) participated in the 5-year in-person follow-up visit; 68 children (52%) were male. Fifty-seven of 131 children (44%) had postoperative AKI. At follow-up, 22 children (17%) had hypertension (10 times higher than the published general pediatric population prevalence), while 9 (8%), 13 (13%), and 1 (1%) had microalbuminuria, an eGFR less than 90 mL/min/1.73 m2, and an eGFR less than 60 mL/min/1.73 m2, respectively. Twenty-one children (18%) had chronic kidney disease. Only 5 children (4%) had been seen by a nephrologist during follow-up. There was no significant difference in renal outcomes between children with and without postoperative AKI. Conclusions and Relevance: Chronic kidney disease and hypertension are common 5 years after pediatric cardiac surgery. Perioperative AKI is not associated with these complications. Longer follow-up is needed to ascertain resolution or worsening of chronic kidney disease and hypertension. PMID- 27618169 TI - [Conceptual and Cognitive Restructuring?] AB - Objective: In the treatment of patients with alcohol dependence it is next to physical detoxification under protected conditions to promoting abstinence motivation. Further the need of crisis interventions is derived from the clinical practise. To be able to become fairer to all groups of treatment as well as the different demands, the addiction admission station was restructured. Methods: Pre post-evaluation. Results: It was found that the door was closed up significantly less often after the restructuring. In the residence time structure an increase appeared in the descriptive values with the more than 7-day stays. Conclusions: It is to be able to hold successfully the optional closed door highly significantly more often open. PMID- 27618167 TI - Challenges Enrolling Children Into Traumatic Brain Injury Trials: An Observational Study. AB - OBJECTIVES: In preparation for a clinical trial of therapeutic agents for children with moderate-to-severe blunt traumatic brain injuries (TBIs) in emergency departments (EDs), we conducted this feasibility study to (1) determine the number and clinical characteristics of eligible children, (2) determine the timing of patient and guardian arrival to the ED, and (3) describe the heterogeneity of TBIs on computed tomography (CT) scans. METHODS: We conducted a prospective observational study at 16 EDs of children <= 18 years of age presenting with blunt head trauma and Glasgow Coma Scale scores of 3-12. We documented the number of potentially eligible patients, timing of patient and guardian arrival, patient demographics and clinical characteristics, severity of injuries, and cranial CT findings. RESULTS: We enrolled 295 eligible children at the 16 sites over 6 consecutive months. Cardiac arrest and nonsurvivable injuries were the most common characteristics that would exclude patients from a future trial. Most children arrived within 2 hours of injury, but most guardians did not arrive until 2-3 hours after the injury. There was a substantial range in types of TBIs, with subdural hemorrhages being the most common. CONCLUSION: Enrolling children with moderate-to-severe TBI into time-sensitive clinical trials will require large numbers of sites and meticulous preparation and coordination and will prove challenging to obtain informed consent given the timing of patient and guardian arrival. The Federal Exception from Informed Consent for Emergency Research will be an important consideration for enrolling these children. PMID- 27618170 TI - [Negotiating the Space Between Openness and Rejection - Mental Health Nurses' Attitudes Towards Risk Behaviour of their Patients - A Qualitative Study]. AB - Objective Personal recovery as a key concept in mental health requests that people with severe mental illness need support in taking positive risks, especially from mental health nurses as key players in this context. In German speaking countries, studies regarding positive risk-taking seem scarce. Attitude as a concept of social psychology seems to be important to this topic, because it strongly influences the human behavior. Therefore, this study examines the attitudes of mental health nurses in outpatient settings towards their patients taking positive risks and their perception of the institutional position regarding this issue. Methods Four focus group interviews were conducted and analyzed using a descriptive content-analysis approach. Results Three main categories were identified: the concept of risk, the nurses' ambivalence and the institutions' ambivalence. Nurses seem to generally connote risk negatively. Their attitudes towards positive risks can be described as ambivalent, oscillating between openness and aversion and their institutions perceive it similarly. Conclusion Results from other studies can be confirmed. Nurses expect clear position from their institution regarding positive risk-taking and increased support. Guidelines are missing in practice. PMID- 27618171 TI - [Dealing with Parenthood among Mental Health Service Users During Inpatient Treatment: Mental Health Professionals' Perspectives to Barriers and Facilitators]. AB - Study aims To gain insight into mental health professionals' subjective perceptions of parenthood among psychiatric patients during inpatient treatment. Methods 31 problem-centered semi-structured interviews with psychiatric professionals were conducted and analyzed by content analysis methods. Results From participants' perspectives, parenthood issues are mainly relevant during hospital admission when child care has to be secured. Participants reported the following barriers: sickness aspects, fears of patients, lack of time and professional knowledge on parenthood issues in clinical care. Discussion Structural barriers which hinder consideration of parenthood issues beyond hospital admission should be reduced. PMID- 27618172 TI - [Emergency Doctor Training for Psychiatric Emergencies: Evaluation of an Interactive Training Program]. AB - Aim Emergency physicians are often confronted with psychiatric emergencies, but are not well trained for it and often feel unable to cope sufficiently with them. The aim of this investigation was to examine whether multisensoric training may improve learning effects in the training of emergency physicians with regard to psychiatric emergencies. Method Participation in a multi-modal, multi-media training program with video case histories and subsequent evaluation by questionnaire. Results 66 emergency physicians assessed their learning effects. 75 % or 73 % rated it as "rather high" or "very high". In particular, in comparison with classical training/self-study 89 % assessed the effects in learning as "rather high" or "very high" . Conclusion This training receives a high level of acceptance. Using videos, learning content may be provided more practice-related. Thus, emergency physicians are able to develop a greater understanding of psychiatric emergencies. PMID- 27618173 TI - [Quality Indicators for Integrated Care in Patients with Schizophrenia - Results from a Feasibility Study]. AB - Objective The study aimed to evaluate the applicability of a set of quality indicators to assess models of integrated care for patients with a diagnosis of schizophrenia. We report first values for these indicators in routine care in Germany. Methods The study is based on a cohort of adult patients with schizophrenia insured by one large German statutory health insurance company, which were assessed two times and gave consent to evaluate their routine claims data. The study tried to use 12 basic and 22 quality indicators from claims data. Results It was possible to estimate most structural indicators using available data, but only half of the quality indicators. This means that while assessment of quality indicators is feasible in general, routine claims data needs to be supplemented by additional (primary) data. Four of the calculated quality indicators had clear targets or red-flag values, which were not met in our cohort in all four indicators. None of the patients had an outpatient mental health related contact within one week (target > 90 %). The readmission rate within 30 days (21 %) was twice as high as the proposed red-flag value of 10 %. Similar figures were seen for antipsychotic polypharmacy (25 %, red-flag value > 10 %) and the proportion of patients with compulsory treatment (15 %) exceeded the red flag value by 5 %. Conclusion The study shows that it is possible to measure quality indicators, but also demonstrates considerable limitations. There is a need to validate indicators in routine care. PMID- 27618174 TI - [Psychometric Properties of the Self- and Observer-Ratings ADHD-SR and Wender Reimherr-Interview in the Assessment of ADHD Symptoms in Old Age]. AB - Objective and Methods The aim of the study was to explore the psychometric properties of the ADHD self-rating ADHD-SR and the observer-rating Wender Reimherr-Interview WRI for the assessment of ADHD symptoms in old age by using a sample of 324 subjects between 60 and 99 years. Results In the sample of older people the psychometric properties of the ADHD-SR and the WRI were adequate. Evidence for construct validity is provided through the WRI. Results of logistic analysis's showed a good discrimination of ADHD for both, the ADHD-SR (89.5 % correct classification; OR = 25.91) and the WRI (86.1 % correct classification; OR = 4.7); specificity ranged between 81 % and 94 %. Conclusion The study shows that both, the ADHD-SR and the WRI, are reliable and valid as tools for the assessment of ADHD in older adults. PMID- 27618175 TI - [Facing Strangeness: Perceptions of Men Whose Partners Became Mentally Ill After Delivering a Baby]. AB - Objective This study explores men's perceptions of their partners' postpartum psychiatric disorders and their experiences of acute mental health care. Methods Interviews were conducted with 13 men who had experienced postpartum psychiatric disorders of their partners. Data were analysed using grounded theory methodology. Results Fathers were affected by their partners' postpartum psychiatric disorder and inpatient treatment. The core category found is the experience of strangeness. The men were faced with a changed partner, an unknown disorder and a confusing mental health care system. Conclusion Fathers wanted to support their partners but felt rarely noticed by mental health care providers. Increased awareness of fathers' needs, such as being informed and involved in their partner's care planning, is recommended to promote the whole family system. PMID- 27618176 TI - [Regional Budgets in Psychiatry: An Alternative to Hospital per Diem Charges and the New Reimbursement System? - A Case Study from the District of Dithmarschen]. AB - Objective The study looked at the impact that the switch from a reimbursement system with hospital per diem charges to a regional budget had on treatment. Methods Routine data from two clinics over a period of ten years were evaluated. Results Treatment took place in day clinics and on an outpatient basis to an increased extent after the change. Conclusion The change in reimbursement system was the cause of the change in treatment. Since similar effects can also be expected when switching from the new reimbursement system for psychiatry and psychosomatic medicine to a regional budget system, regional budgets are a reasonable alternative. PMID- 27618178 TI - Gain-of-Function Alleles in Caenorhabditis elegans Nuclear Hormone Receptor nhr 49 Are Functionally Distinct. AB - Nuclear hormone receptors (NHRs) are transcription factors that regulate numerous physiological and developmental processes and represent important drug targets. NHR-49, an ortholog of Hepatocyte Nuclear Factor 4 (HNF4), has emerged as a key regulator of lipid metabolism and life span in the nematode worm Caenorhabditis elegans. However, many aspects of NHR-49 function remain poorly understood, including whether and how it regulates individual sets of target genes and whether its activity is modulated by a ligand. A recent study identified three gain-of-function (gof) missense mutations in nhr-49 (nhr-49(et7), nhr-49(et8), and nhr-49(et13), respectively). These substitutions all affect the ligand binding domain (LBD), which is critical for ligand binding and protein interactions. Thus, these alleles provide an opportunity to test how three specific residues contribute to NHR-49 dependent gene regulation. We used computational and molecular methods to delineate how these mutations alter NHR-49 activity. We find that despite originating from a screen favoring the activation of specific NHR-49 targets, all three gof alleles cause broad upregulation of NHR 49 regulated genes. Interestingly, nhr-49(et7) and nhr-49(et8) exclusively affect nhr-49 dependent activation, whereas the nhr-49(et13) surprisingly affects both nhr-49 mediated activation and repression, implicating the affected residue as dually important. We also observed phenotypic non-equivalence of these alleles, as they unexpectedly caused a long, short, and normal life span, respectively. Mechanistically, the gof substitutions altered neither protein interactions with the repressive partner NHR-66 and the coactivator MDT-15 nor the subcellular localization or expression of NHR-49. However, in silico structural modeling revealed that NHR-49 likely interacts with small molecule ligands and that the missense mutations might alter ligand binding, providing a possible explanation for increased NHR-49 activity. In sum, our findings indicate that the three nhr 49 gof alleles are non-equivalent, and highlight the conserved V411 residue affected by et13 as critical for gene activation and repression alike. PMID- 27618179 TI - Longitudinal Investigation into Genetics in the Conservation of Metabolic Phenotypes in Danish and Chinese Twins. AB - Longitudinal twin studies on long term conservation of individual metabolic phenotypes can help to explore the genetic and environmental basis in maintaining metabolic homeostasis and metabolic health. We performed a longitudinal twin study on 12 metabolic phenotypes from Danish twins followed up for 12 years and Chinese twins traced for 7 years. The study covered a relatively large sample of 502 pairs of Danish adult twins with a mean age at intake of 38 years and a total of 181 Chinese adult twin pairs with a mean baseline age of 39.5 years. Bivariate twin models were fitted to the longitudinal measurements taken at two time points (at baseline and follow-up) to estimate the genetic and environmental contributions to phenotype variation and correlation at and between the two time points. High genetic components in the regulation of intra-individual phenotype correlation or stability over time were estimated in both Danish (h2>0.75 except fasting blood glucose) and Chinese (h2>0.72 except blood pressure) twins; moderate to high genetic contribution to phenotype variation at the two time points were also estimated except for the low genetic regulation on glucose in Danish and on blood pressure in Chinese twins. Meanwhile the bivariate twin models estimated shared environmental contributions to the variance and covariance in fasting blood glucose in Danish twins, and in systolic and diastolic blood pressure, low and high density lipoprotein cholesterol in Chinese twins. Overall, our longitudinal twin study on long-term stability of metabolic phenotypes in Danish and Chinese twins identified a common pattern of high genetic control over phenotype conservation, and at the same time revealed population-specific patterns of genetic and common environmental regulation on the variance as well as covariance of glucose and blood pressure. PMID- 27618180 TI - Adoptive Immunotherapy in Postoperative Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Adoptive immunotherapy (AI) has been applied in the treatment of non small-cell lung cancer (NSCLC) patients, but the value of postoperative AI has been inconclusive largely as a result of the small number of patients included in each study. We performed a systematic review and meta-analysis to address this issue for patients with postoperative NSCLC. METHODS: Pubmed, Embase, Cochrane Library were searched for randomized controlled trials comparing adoptive immunotherapy with control therapies in postoperative NSCLC patients. The primary endpoint was overall survival. Hazard ratio (HR) was estimated and 95% confidence intervals (CI) were calculated using a fixed-effect model. RESULTS: Compared with control therapies, analyses of 4 randomized controlled trials (472 patients) showed a significant benefit of adoptive immunotherapy on survival (hazard ratio [HR] 0.61, 95% CI 0.45-0.84, p = 0.002), and a 39% reduction in the relative risk of death (no evidence of a difference between trials; p = 0.16, I2 = 42%). In subgroup analyses by treatment cycles and treatment regimen, significant OS benefit was found in combination therapy of AI with chemotherapy, regardless of whether or not the treatment cycles were more than 10 cycles. CONCLUSION: Adoptive immunotherapy has the potential to improve overall survival in postoperative NSCLC. The findings suggest this is a valid treatment option for these patients. Further randomized clinical trials are urgently needed. PMID- 27618181 TI - Prevalence and Predictors of Depression among Pregnant Women in Debretabor Town, Northwest Ethiopia. AB - BACKGROUND: Depression during pregnancy is a major health problem because it is prevalent and chronic, and its impact on birth outcome and child health is serious. Several psychosocial and obstetric factors have been identified as predictors. Evidence on the prevalence and predictors of antenatal depression is very limited in Ethiopia. This study aims to determine prevalence and associated factors with antenatal depression. METHODS: Community based cross-sectional study was conducted among 527 pregnant women recruited in a cluster sampling method. Data were collected by face-to-face interviews on socio-demographic, obstetric, and psychosocial characteristics. Depression symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS). The List of Threatening Experiences questionnaire (LTE-Q) and the Oslo Social Support Scale (OSS-3) were used to assess stressful events and social support, respectively. Data were entered into Epi-info and analyzed using SPSS-20. Descriptive and logistic regression analyses were carried out. RESULTS: The prevalence of antenatal depression was found to be 11.8%. Having debt (OR = 2.79, 95% CI = 1.33, 5.85), unplanned pregnancy (OR = 2.39, 95% CI = (1.20, 4.76), history of stillbirth (OR = 3.97, 95% CI = (1.67,9.41), history of abortion (OR = 2.57, 95% CI = 1.005, 6.61), being in the third trimester of pregnancy (OR = 1.70, 95% CI = 1.07,2.72), presence of a complication in the current pregnancy (OR = 3.29, 95% CI = 1.66,6.53), and previous history of depression (OR = 3.48, 95% CI = 1.71,7.06) were factors significantly associated with antenatal depression. CONCLUSION: The prevalence of antenatal depression was high, especially in the third trimester. Poverty, unmet reproductive health needs, and obstetric complications are the main determinants of antenatal depression. For early detection and appropriate intervention, screening for depression during the routine antenatal care should be promoted. PMID- 27618183 TI - Different Respiratory Rates during Resuscitation in a Pediatric Animal Model of Asphyxial Cardiac Arrest. AB - AIMS: Actual resuscitation guidelines recommend 10 respirations per minute (rpm) for advanced pediatric life support. This respiratory rate (RR) is much lower than what is physiological for children. The aim of this study is to compare changes in ventilation, oxygenation, haemodynamics and return of spontaneous circulation (ROSC) rates with three RR. METHODS: An experimental model of asphyxial cardiac arrest (CA) in 46 piglets (around 9.5 kg) was performed. Resuscitation with three different RR (10, 20 and 30 rpm) was carried out. Haemodynamics and gasometrical data were obtained at 3, 9, 18 and 24 minutes after beginning of resuscitation. Measurements were compared between the three groups. RESULTS: No statistical differences were found in ROSC rate between the three RR (37.5%, 46.6% and 60% in the 10, 20 and 30 rpm group respectively P = 0.51). 20 and 30 rpm groups had lower PaCO2 values than 10 rpm group at 3 minutes (58 and 55 mmHg vs 75 mmHg P = 0.08). 30 rpm group had higher PaO2 (61 mmHg) at 3 minutes than 20 and 10 rpm groups (53 and 45 mmHg P = 0.05). No significant differences were found in haemodynamics or tissue perfusion between hyperventilated (PaCO2 <30 mmHg), normoventilated (30-50 mmHg) and hypoventilated (>50 mmHg) animals. PaO2 was significantly higher in hyperventilated (PaO2 153 mmHg) than in normoventilated (79 mmHg) and hypoventilated (47 mmHg) piglets (P<0.001). CONCLUSIONS: Our study confirms the hypothesis that higher RR achieves better oxygenation and ventilation without affecting haemodynamics. A higher RR is associated but not significantly with better ROSC rates. PMID- 27618185 TI - Rapid Bacterial Detection via an All-Electronic CMOS Biosensor. AB - The timely and accurate diagnosis of infectious diseases is one of the greatest challenges currently facing modern medicine. The development of innovative techniques for the rapid and accurate identification of bacterial pathogens in point-of-care facilities using low-cost, portable instruments is essential. We have developed a novel all-electronic biosensor that is able to identify bacteria in less than ten minutes. This technology exploits bacteriocins, protein toxins naturally produced by bacteria, as the selective biological detection element. The bacteriocins are integrated with an array of potassium-selective sensors in Complementary Metal Oxide Semiconductor technology to provide an inexpensive bacterial biosensor. An electronic platform connects the CMOS sensor to a computer for processing and real-time visualization. We have used this technology to successfully identify both Gram-positive and Gram-negative bacteria commonly found in human infections. PMID- 27618184 TI - Combined Analysis of Variation in Core, Accessory and Regulatory Genome Regions Provides a Super-Resolution View into the Evolution of Bacterial Populations. AB - The use of whole-genome phylogenetic analysis has revolutionized our understanding of the evolution and spread of many important bacterial pathogens due to the high resolution view it provides. However, the majority of such analyses do not consider the potential role of accessory genes when inferring evolutionary trajectories. Moreover, the recently discovered importance of the switching of gene regulatory elements suggests that an exhaustive analysis, combining information from core and accessory genes with regulatory elements could provide unparalleled detail of the evolution of a bacterial population. Here we demonstrate this principle by applying it to a worldwide multi-host sample of the important pathogenic E. coli lineage ST131. Our approach reveals the existence of multiple circulating subtypes of the major drug-resistant clade of ST131 and provides the first ever population level evidence of core genome substitutions in gene regulatory regions associated with the acquisition and maintenance of different accessory genome elements. PMID- 27618186 TI - The haptic pleasures of ground-feel: The role of textured terrain in motivating regular exercise. AB - This paper explores the role that somatic or bodily touch-based experience of ground surface textures plays in securing a commitment to health-giving exercise practices, and argues that ground-feel is a neglected and underrated dimension of how environments co-constitute health. Past work has largely either overlooked ground-feel or positioned rough ground solely as a barrier to bodily movement. This research, however, informed by mobile and video ethnographies of walking and mountain biking in Scotland, elaborates a number of ways in which the experience of textured terrain can produce sensory and emotional experiences that motivate regular exercise. The possibility of positive tactile as well as visual experiences of landscapes, including uneven as well as smooth surfaces, ought then to be taken more seriously in designing everyday outdoor environments that encourage the energetic movement of bodies. A key challenge is to identify the optimal mix of textured and smooth ground surfaces to encourage increased energetic engagement for the widest range of users. PMID- 27618187 TI - Lactate metabolism is associated with mammalian mitochondria. AB - It is well established that lactate secreted by fermenting cells can be oxidized or used as a gluconeogenic substrate by other cells and tissues. It is generally assumed, however, that within the fermenting cell itself, lactate is produced to replenish NAD+ and then is secreted. Here we explore the possibility that cytosolic lactate is metabolized by the mitochondria of fermenting mammalian cells. We found that fermenting HeLa and H460 cells utilize exogenous lactate carbon to synthesize a large percentage of their lipids. Using high-resolution mass spectrometry, we found that both 13C and 2-2H labels from enriched lactate enter the mitochondria. The lactate dehydrogenase (LDH) inhibitor oxamate decreased respiration of isolated mitochondria incubated in lactate, but not of isolated mitochondria incubated in pyruvate. Additionally, transmission electron microscopy (TEM) showed that LDHB localizes to the mitochondria. Taken together, our results demonstrate a link between lactate metabolism and the mitochondria of fermenting mammalian cells. PMID- 27618188 TI - How the glycosyltransferase OGT catalyzes amide bond cleavage. AB - The essential human enzyme O-linked beta-N-acetylglucosamine transferase (OGT), known for modulating the functions of nuclear and cytoplasmic proteins through serine and threonine glycosylation, was unexpectedly implicated in the proteolytic maturation of the cell cycle regulator host cell factor-1 (HCF-1). Here we show that HCF-1 cleavage occurs via glycosylation of a glutamate side chain followed by on-enzyme formation of an internal pyroglutamate, which undergoes spontaneous backbone hydrolysis. PMID- 27618189 TI - The role of protein dynamics in the evolution of new enzyme function. AB - Enzymes must be ordered to allow the stabilization of transition states by their active sites, yet dynamic enough to adopt alternative conformations suited to other steps in their catalytic cycles. The biophysical principles that determine how specific protein dynamics evolve and how remote mutations affect catalytic activity are poorly understood. Here we examine a 'molecular fossil record' that was recently obtained during the laboratory evolution of a phosphotriesterase from Pseudomonas diminuta to an arylesterase. Analysis of the structures and dynamics of nine protein variants along this trajectory, and three rationally designed variants, reveals cycles of structural destabilization and repair, evolutionary pressure to 'freeze out' unproductive motions and sampling of distinct conformations with specific catalytic properties in bi-functional intermediates. This work establishes that changes to the conformational landscapes of proteins are an essential aspect of molecular evolution and that change in function can be achieved through enrichment of preexisting conformational sub-states. PMID- 27618192 TI - Further Characterization of Genetically Distinct Groups of Acidovorax citrulli Strains. AB - Bacterial fruit blotch of cucurbits (BFB) is caused by the gram-negative bacterium Acidovorax citrulli, whose populations can be distinguished into two genetically distinct groups, I and II. Based on visual assessment of BFB severity on cucurbit seedlings and fruit after inoculation under greenhouse conditions, group I A. citrulli strains have been reported to be moderately to highly virulent on several cucurbit hosts, whereas group II strains have exhibited high virulence on watermelon but low virulence on other cucurbits. Additionally, group I strains are recovered from a range of cucurbit hosts, while group II strains are predominantly found on watermelon. The goal of this research was to develop tools to characterize and rapidly distinguish group I and II A. citrulli strains. We first sought to determine whether quantification of A. citrulli colonization of cucurbit seedling tissue reflects the differences between group I and II strains established by visual assessment of BFB symptom severity. Spray inoculation of melon seedlings with cell suspensions containing approximately 1 * 104 CFU/ml resulted in significantly higher (P = 0.01) population growth of M6 (group I; mean area under population growth curve [AUPGC] = 43.73) than that of AAC00-1 (group II; mean AUPGC = 39.33) by 10 days after inoculation. We also investigated the natural spread of bacterial cells and the resulting BFB incidence on watermelon and melon seedlings exposed to three group I and three group II A. citrulli strains under mist chamber conditions. After 5 days of exposure, the mean BFB incidence on melon seedlings exposed to representative group II A. citrulli strains was significantly lower (25 and 3.98% in experiments 1 and 2, respectively) than on melon seedlings exposed to representative group I strains (94.44 and 76.11% in experiments 1 and 2, respectively), and on watermelon seedlings exposed to representative group I and II strains (70 to 93.33%). Finally, we developed a polymerase chain reaction assay based on the putative type III secretion effector gene, Aave_2166, to rapidly distinguish group I and II A. citrulli strains. This assay will be important for future epidemiological studies on BFB. PMID- 27618193 TI - Phenomic Approaches and Tools for Phytopathologists. AB - Plant phenomics approaches aim to measure traits such as growth, performance, and composition of plants using a suite of noninvasive technologies. The goal is to link phenotypic traits to the genetic information for particular genotypes, thus creating the bridge between the phenome and genome. Application of sensing technologies for detecting specific phenotypic reactions occurring during plant pathogen interaction offers new opportunities for elucidating the physiological mechanisms that link pathogen infection and disease symptoms in the host, and also provides a faster approach in the selection of genetic material that is resistant to specific pathogens or strains. Appropriate phenomics methods and tools may also allow presymptomatic detection of disease-related changes in plants or to identify changes that are not visually apparent. This review focuses on the use of sensor-based phenomics tools in plant pathology such as those related to digital imaging, chlorophyll fluorescence imaging, spectral imaging, and thermal imaging. A brief introduction is provided for less used approaches like magnetic resonance, soft x-ray imaging, ultrasound, and detection of volatile compounds. We hope that this concise review will stimulate further development and use of tools for automatic, nondestructive, and high-throughput phenotyping of plant-pathogen interaction. PMID- 27618190 TI - A chemical-inducible CRISPR-Cas9 system for rapid control of genome editing. AB - CRISPR-Cas9 has emerged as a powerful technology that enables ready modification of the mammalian genome. The ability to modulate Cas9 activity can reduce off target cleavage and facilitate precise genome engineering. Here we report the development of a Cas9 variant whose activity can be switched on and off in human cells with 4-hydroxytamoxifen (4-HT) by fusing the Cas9 enzyme with the hormone binding domain of the estrogen receptor (ERT2). The final optimized variant, termed iCas, showed low endonuclease activity without 4-HT but high editing efficiency at multiple loci with the chemical. We also tuned the duration and concentration of 4-HT treatment to reduce off-target genome modification. Additionally, we benchmarked iCas against other chemical-inducible methods and found that it had the fastest on rate and that its activity could be toggled on and off repeatedly. Collectively, these results highlight the utility of iCas for rapid and reversible control of genome-editing function. PMID- 27618194 TI - Management of knee osteoarthritis. Current status and future trends. AB - Osteoarthritis (OA) affects a large number of the population, and its incidence is showing a growing trend with the increasing life span. OA is the most prevalent joint condition worldwide, and currently, there is no functional cure for it. This review seeks to briefly overview the management of knee OA concerning standardized pharmaceutical and clinical approaches, as well as the new biotechnological horizons of OA treatment. The potential of biomaterials and state of the art of advanced therapeutic approaches, such as cell and gene therapy focused primarily on cartilage regeneration are the main subjects of this review. Biotechnol. Bioeng. 2017;114: 717-739. (c) 2016 Wiley Periodicals, Inc. PMID- 27618195 TI - Overweight and Obesity in Young Adulthood and the Risk of Stroke: a Meta analysis. AB - BACKGROUND: A systematic review assessing the association between overweight and obesity in young adulthood and stroke risk is lacking. Therefore, we conducted a meta-analysis to evaluate the association between overweight and obesity in young adulthood and stroke risk. METHODS: We systematically searched PubMed and Embase databases for related studies of human subjects in the English language. Two investigators independently selected original studies in a 2-step process. Fixed- and random-effects models were used to calculate pooled relative risks (RRs) and 95% confidence intervals (CIs). Subgroup analyses were also performed. RESULTS: Eight studies met the inclusion criteria. The pooled adjusted RR of stroke was 1.36 (95% CI: 1.28-1.44) for overweight in young adulthood and 1.81 (95% CI: 1.45 2.25) for obesity in young adulthood. In subgroup analyses, overweight and obesity in young adulthood increased the risk of stroke in most groups, except for the group of stroke subtype. For ischemic stroke, the adjusted RR was 1.40 (95% CI: 1.24-1.58) for overweight in young adulthood and 1.78 (95% CI: 1.003 3.16) for obesity in young adulthood, whereas adjusted RR for hemorrhagic stroke was 1.25 (95% CI: .83-1.90) for overweight in young adulthood and 1.80 (95% CI: .97-3.35) for obesity in young adulthood. CONCLUSIONS: Overweight and obesity in young adulthood are associated with an increased risk of stroke, probably, independent of other cardiovascular risk factors. The risk effect gradually increases with increasing body weight. PMID- 27618196 TI - Gender Differences in Exclusion Criteria for Recombinant Tissue-Type Plasminogen Activator. AB - BACKGROUND: Gender differences in the use of recombinant tissue-type plasminogen activator (r-tPA) in stroke are complicated. In this study, we investigated gender differences using r-tPA exclusion criterion in a stroke population. METHODS: We analyzed the data from ischemic stroke patients aged 18 years or older from the Greenville Health System stroke registry on r-tPA administration between January 2010 and December 2013. We identified exclusion criterion and used specific clinical factors to determine gender differences in stroke patients receiving r-tPA. RESULTS: Of the 633 patients who were eligible to receive r-tPA, less than half received r-tPA (n = 241) whereas 422 were not able to receive r tPA. Of the 241 patients who received r-tPA, 49.4% were female and 50.6% were male. Of the 422 patients who did not receive r-tPA, more women (235) were excluded from r-tPA than men (187) (P < .05). There were no gender differences in warning signs and contraindications in female versus male stroke patients (P > .005). There were however gender differences in age group as more women (38%; n = 235) were more likely to be excluded if they are more than 80 years old than men (19%, n = 187). CONCLUSIONS: Within a large stroke population, exclusion criteria for r-tPA in women and men were similar with regard to race, initial National Institutes of Health Stroke Scale score, warning signs, and contraindications, but were different in the age group population exclusion criterion for intravenous r-tPA. We observed that intracerebral hemorrhage and match on computed tomography perfusion/magnetic resonance imaging or visible infarct greater than one third of the middle cerebral artery distribution were absolute criteria for exclusion. PMID- 27618198 TI - Prediction of Infarct Lesion Volumes by Processing Magnetic Resonance Apparent Diffusion Coefficient Maps in Patients with Acute Ischemic Stroke. AB - OBJECTIVE: We aimed to investigate the diagnostic value of apparent diffusion coefficient (ADC) maps in magnetic resonance imaging (MRI) in the volume of acute cerebral infarction (ACI). METHODS: A total of 207 ACI patients were selected in our study. The cerebral infarction (CI) volume in the initial diffusion-weighted imaging examination, minimum ADC value, relative apparent diffusion coefficient (rADC) value, and mean ADC value were measured. The correlations between age, smoking, drinking, hypertension, diabetes, coronary heart disease, clinical stage, the lowest ADC value, the mean ADC value, and the mean rADC value with CI volume were analyzed by logistic regression analysis. A receiver operating characteristic (ROC) curve was used to analyze the diagnostic value of the ADC value in the ACI volume. RESULTS: There was a significant difference in the distribution of the CI volume in ACI patients (P <.05). A significant difference was found in the signal intensity and percentage distribution of ADC map in patients of different CI groups with different CI volumes (P <.05). The signal of the ADC map was positively correlated with the CI volume. The mean ADC and rADC values had significant differences between different CI volumes (all P <.05). Logistic regression analysis revealed that the mean ADC value was significantly correlated with the CI volume (P <.05). Analysis of the ROC curve showed that the quantitative value of ADC has a diagnostic value for the ACI volume. CONCLUSION: This study has shown that the signal intensity change on the ADC map in MRI and quantitative analysis of the ADC value can be used as a reference for predicting the ACI volume. PMID- 27618197 TI - Time to Computerized Tomography Scan, Age, and Mortality in Acute Stroke. AB - BACKGROUND: Time to computerized tomography (CT) is important to institute appropriate and timely hyperacute management in stroke. We aimed to evaluate mortality outcomes in relation to age and time to CT scan. METHODS: We used routinely collected data in 8 National Health Service trusts in East of England between September 2008 and April 2011. Stroke cases were prospectively identified and confirmed. Odds ratios (ORs) for unadjusted and adjusted models for age categories (<65, 65-74, 75-84, and >=85 years) as well as time to CT categories (<90 minutes, >=90 to <180 minutes, >=180 minutes to 24 hours, and >24 hours) and in-hospital and early (<7 days) mortality outcomes were calculated. RESULTS: Of the 7693 patients (mean age 76.1 years, 50% male) included, 1151 (16%) died as inpatients and 336 (4%) died within 7 days. Older patients and those admitted from care home had a significantly longer time from admission until CT (P < .001). Patients who had earlier CT scans were admitted to stroke units more frequently (P < .001) but had higher in-patient (P < .001) and 7-day mortality (P < .001). Whereas older age was associated with increased odds of mortality outcomes, longer time to CT was associated with significantly reduced mortality within 7 days (corresponding ORs for the above time periods were 1.00, .61 [95% confidence interval {CI}: .39-.95], .39 [.24-.64], and .16 [.08-.33]) and in hospital mortality (ORs 1.00, .86 [.64-1.15], .57 [.42-.78] and .71 [.52-.98]). CONCLUSIONS: Older age was associated with a significantly longer time to CT. However, using CT scan time as a benchmarking tool in stroke may have inherent limitations and does not appear to be a suitable quality marker. PMID- 27618200 TI - Photochemical Synthesis of Both Strained and Macrocyclic (1,7)Naphthalenophanes. AB - Naphthalenophanes are a special type of cyclophanes. While in the past (1,5)-, (1,6)-, and (1,8)naphthalenophanes were successfully prepared by using the photo dehydro-Diels-Alder (DDA) reaction, access to (1,7)naphthalenophanes by this method was hitherto unknown. After numerous unsuccessful attempts to prepare these compounds by thermal DDA, we found that the photoinitiated variant (PDDA) represents a very efficient method to [k](1,7)naphthalenophanes 13. The scope ranged from highly strained (k = 11, 12) to macrocyclic products (k = 22, 24). The extraordinary reactivity could be explained by folded ground-state geometries of diketones 12 used as reactants of the PDDA. Furthermore, we calculated the ring-strain energies with the help of an isodesmic reaction and evaluated structural and spectroscopic (NMR) consequences of ring strain. PMID- 27618199 TI - Prolonged Corrected QT Interval as a Predictor of Clinical Outcome in Acute Ischemic Stroke. AB - BACKGROUND: This study aimed to investigate changes of corrected QT (QTc) interval during acute ischemic stroke and its correlation with high-sensitivity troponin I (hsTnI), brain natriuretic peptide (BNP), neurological outcome, and 1 year mortality. METHODS: We registered electrocardiogram in 69 patients immediately after admission to the intensive care unit and then after 24 and 48 hours. Computed tomography was performed on admission to determine brain infarct size and localization. Neurological outcome was assessed by modified Rankin scale (mRS) at discharge. RESULTS: Forty-five (65.2%) patients had prolonged QTc at baseline; only 18 (26.1%) patients had prolonged QTc after 48 hours. Baseline QTc was not associated with neurological outcome (P = .27). However, prolonged QTc after 48 hours was associated with worse mRS at discharge (4.5 [4.0-6.0] versus 2.0 [1.0-3.0]; P < .0001). Patients who deceased during hospitalization (n = 7 [10.1%]) as compared with survivors had more frequently prolonged QTc after 48 hours (38.9 versus 0%; P < .0001), higher level of hsTnI (48.4 [36.1-75.0] versus 8.6 [3.4-26.5]; P = .003), and BNP (334 [224-866] versus 109 [30-190]; P = .014). In univariate analysis, 1-year mortality was associated with prolonged QTc after 48 hours, hsTnI, and BNP. In multivariate analysis, only BNP remained to be associated with 1-year mortality (odds ratio 3.41, 95% confidence interval 1.06 11.03). CONCLUSIONS: QTc interval in patients with acute ischemic stroke is a dynamic parameter. Prolonged QTc after 48 hours, but not baseline QTc, correlated with neurological outcome and 1-year mortality. Patients with prolonged QTc had higher level of hsTnI. PMID- 27618201 TI - Aminoglycoside-stimulated readthrough of premature termination codons in selected genes involved in primary ciliary dyskinesia. AB - Translational readthrough of premature termination codons (PTCs) induced by pharmacological compounds has proven to be an effective way of restoring functional protein expression and reducing symptoms in several genetic disorders. We tested the potential of different concentrations of several aminoglycosides (AAGs) for promoting PTC-readthrough in 5 genes involved in the pathogenesis of primary ciliary dyskinesia, an inherited disorder caused by the dysfunction of motile cilia and flagella. The efficiency of readthrough stimulation of PTCs cloned in dual reporter vectors was examined in 2 experimental settings: in vitro (transcription/translation system) and ex vivo (transiently transfected epithelial cell line). PTC-readthrough was observed in 5 of the 16 mutations analyzed. UGA codons were more susceptible to AAG-stimulated readthrough than UAG; no suppression of UAA was observed. The efficiency of PTC-readthrough in vitro (from less than 1% to ~28% of the translation from the corresponding wild type constructs) differed with the AAG type and concentration, and depended on the combination of AAG and PTC, indicating that each PTC has to be individually tested with a range of stimulating compounds. The maximal values of PTC suppression observed in the ex vivo experiments were, depending on AAG used, 3-5 times lower than the corresponding values in vitro, despite using AAG concentrations that were 2 orders of magnitude higher. This indicates that, while the in vitro system is sufficient to examine the readthrough-susceptibility of PTCs, it is not sufficient to test the compounds potential to stimulate PTC readthrough in the living cells. Most of the tested compounds (except for G418) at their highest concentrations did not disturb ciliogenesis in the cultures of primary respiratory epithelial cells from healthy donors. PMID- 27618202 TI - Communicating the results of criterion referenced prediction measures: Risk categories for the Static-99R and Static-2002R sexual offender risk assessment tools. AB - This article describes principles for developing risk category labels for criterion referenced prediction measures, and demonstrates their utility by creating new risk categories for the Static-99R and Static-2002R sexual offender risk assessment tools. Currently, risk assessments in corrections and forensic mental health are typically summarized in 1 of 3 words: low, moderate, or high. Although these risk labels have strong influence on decision makers, they are interpreted differently across settings, even among trained professionals. The current article provides a framework for standardizing risk communication by matching (a) the information contained in risk tools to (b) a broadly applicable classification of "riskiness" that is independent of any particular offender risk scale. We found that the new, common STATIC risk categories not only increase concordance of risk classification (from 51% to 72%)-they also allow evaluators to make the same inferences for offenders in the same category regardless of which instrument was used to assign category membership. More generally, we argue that the risk categories should be linked to the decisions at hand, and that risk communication can be improved by grounding these risk categories in evidence based definitions. (PsycINFO Database Record PMID- 27618203 TI - Revised scoring and improved reliability for the Communication Patterns Questionnaire. AB - The Communication Patterns Questionnaire (CPQ; Christensen, 1987) is a widely used self-report measure of couple communication behavior and is well validated for assessing the demand/withdraw interaction pattern, which is a robust predictor of poor relationship and individual outcomes (Schrodt, Witt, & Shimkowski, 2014). However, no studies have examined the CPQ's factor structure using analytic techniques sufficient by modern standards, nor have any studies replicated the factor structure using additional samples. Further, the current scoring system uses fewer than half of the total items for its 4 subscales, despite the existence of unused items that have content conceptually consistent with those subscales. These characteristics of the CPQ have likely contributed to findings that subscale scores are often troubled by suboptimal psychometric properties such as low internal reliability (e.g., Christensen, Eldridge, Catta Preta, Lim, & Santagata, 2006). The present study uses exploratory and confirmatory factor analyses on 4 samples to reexamine the factor structure of the CPQ to improve scale score reliability and to determine if including more items in the subscales is warranted. Results indicate that a 3-factor solution (constructive communication and 2 demand/withdraw scales) provides the best fit for the data. That factor structure was confirmed in the replication samples. Compared with the original scales, the revised scales include additional items that expand the conceptual range of the constructs, substantially improve reliability of scale scores, and demonstrate stronger associations with relationship satisfaction and sensitivity to change in therapy. Implications for research and treatment are discussed. (PsycINFO Database Record PMID- 27618205 TI - little sister: An Afro-Temporal Solo-Play. AB - little sister: An Afro-Temporal Solo-Play is at once a memory-scape and a mytho biography set to poetry, movement, and mixed media. A performance poem spanning from the Antebellum South to present-moment Chicago, it tells the story of a nomadic spirit named little-she who shape-shifts through the memories and imaginings of her sister, the narrator. Through the characters little-she and the narrator, the solo-performance explores embodied ways to rupture and relieve the impact of macro forms of violence in the micro realm of the everyday. To this end, little sister witnesses and disrupts the legacy of violence in the lives of queer Black women through a trans-temporal navigation of everyday encounters within familial, small groups and intimate partner spaces. PMID- 27618204 TI - Bioactive Formylated Flavonoids from Eugenia rigida: Isolation, Synthesis, and X ray Crystallography. AB - Two new flavonoids, rac-6-formyl-5,7-dihydroxyflavanone (1) and 2',6'-dihydroxy 4'-methoxy-3'-methylchalcone (2), together with five known derivatives, rac-8 formyl-5,7-dihydroxyflavanone (3), 4',6'-dihydroxy-2'-methoxy-3' methyldihydrochalcone (4), rac-7-hydroxy-5-methoxy-6-methylflavanone (5), 3' formyl-2',4',6'-trihydroxy-5'-methyldihydrochalcone (6), and 3'-formyl-2',4',6' trihydroxydihydrochalcone (7), were isolated from the leaves of Eugenia rigida. The individual (S)- and (R)-enantiomers of 1 and 3, together with the corresponding formylated flavones 8 (6-formyl-5,7-dihydroxyflavone) and 9 (8 formyl-5,7-dihydroxyflavone), as well as 2',4',6'-trihydroxychalcone (10), 3' formyl-2',4',6'-trihydroxychalcone (11), and the corresponding 3'-formyl-2',4',6' trihydroxydihydrochalcone (7) and 2',4',6'-trihydroxydihydrochalcone (12), were synthesized. The structures of the isolated and synthetic compounds were established via NMR, HRESIMS, and electronic circular dichroism data. In addition, the structures of 3, 5, and 8 were confirmed by single-crystal X-ray diffraction crystallography. The isolated and synthetic flavonoids were evaluated for their antimicrobial and cytotoxic activities against a panel of microorganisms and solid tumor cell lines. PMID- 27618206 TI - Associations Between Cardiorespiratory Fitness and Overweight With Academic Performance in 12-Year-Old Brazilian Children. AB - : Obesity has been associated with poor academic achievement, while cardiorespiratory fitness (CRF) has been linked to academic success. PURPOSE: To investigate whether CRF is associated with academic performance in Brazilian students, independently of body mass index (BMI), fatness and socioeconomic status (SES). METHODS: 392 5th and 6th grade students (193 girls) (12.11 +/- 0.75 years old) were evaluated in 2012. Skinfold thickness measures were performed, and students were classified according to BMI-percentile. CRF was estimated by a 20-meter shuttle run test, and academic achievement by standardized math and Portuguese tests. Multiple linear regression analyses were conducted to explore the association between academic performance and CRF, adjusted for SES, skinfold thickness or BMI-percentile. RESULTS: Among girls CRF was associated with higher academic achievement in math (beta = 0.146;p = .003) and Portuguese (beta = 0.129;p = .004) in crude and adjusted analyses. No significant association was found among boys. BMI was not associated with overall academic performance. There was a weak negative association between skinfold thickness and performance in mathematics in boys (beta =- 0.030;p = .04), but not in girls. CONCLUSION: The results highlight the importance of maintaining high fitness levels in girls throughout adolescence a period commonly associated with reductions in physical activity levels and CRF. PMID- 27618207 TI - Shape-Memory and Self-Healing Effects in Mechanosalient Molecular Crystals. AB - The thermosalient crystals of terephthalic acid are extraordinarily mechanically compliant and reversibly shape-shift between two forms with different crystal habits. While the transition of form II to form I is spontaneous, the transition of form I to form II is latent and can be triggered by applying local mechanical stress, whereby crystals leap several centimeters in air. This mechanosalient effect (mechanically stimulated motility) is due to sudden release of strain that has accrued in the crystal of form I, which is a metastable structure at ambient conditions. High-speed optical analysis and serial scanning electron microscopy reveal that the mechanical effect is due to rapid reshaping of crystal domains on a millisecond time scale triggered by mechanical stimulation. Mechanically pre deformed crystals taken over the thermal phase transition exhibit memory effects and partially regain their shape, while cracked, sliced, or otherwise damaged crystals tend to recover their macroscopic integrity by restorative action of intermolecular pi-pi interactions in a manner which resembles the behavior of shape-memory and self-healing polymers. These observations provide additional evidence that the thermo-/photo-/mechanosalient effects are macroscopic manifestations of martensitic-type transitions in molecular solids. PMID- 27618209 TI - Atypical modes of bacterial histidine kinase signaling. AB - The environment of a cell has a profound influence on its physiology, development and evolution. Accordingly, the capacity to sense and respond to physical and chemical signals in the environment is an important feature of cellular biology. In bacteria, environmental sensory perception is often regulated by two-component signal transduction systems (TCSTs). Canonical TCST entails signal-induced autophosphorylation of a sensor histidine kinase (HK) followed by phosphoryl transfer to a cognate response regulator (RR) protein, which may affect gene expression at multiple levels. Recent studies provide evidence for systems that do not adhere to this archetypal TCST signaling model. We present selected examples of atypical modes of signal transduction including inactivation of HK activity via homo- and hetero oligomerization, and cross-phosphorylation between HKs. These examples highlight mechanisms bacteria use to integrate environmental signals to control complex adaptive processes. PMID- 27618215 TI - Erratum. PMID- 27618214 TI - Mott transitions in the periodic Anderson model. AB - The periodic Anderson model (PAM) is studied within the framework of dynamical mean-field theory, with particular emphasis on the interaction-driven Mott transition it contains, and on resultant Mott insulators of both Mott-Hubbard and charge-transfer type. The form of the PAM phase diagram is first deduced on general grounds using two exact results, over the full range of model parameters and including metallic, Mott, Kondo and band insulator phases. The effective low energy model which describes the PAM in the vicinity of a Mott transition is then shown to be a one-band Hubbard model, with effective hoppings that are not in general solely nearest neighbour, but decay exponentially with distance. This mapping is shown to have a range of implications for the physics of the problem, from phase boundaries to single-particle dynamics; all of which are confirmed and supplemented by NRG calculations. Finally we consider the locally degenerate, non Fermi liquid Mott insulator, to describe which requires a two-self-energy description. This is shown to yield a number of exact results for the associated local moment, charge, and interaction-renormalised levels, together with a generalisation of Luttinger's theorem to the Mott insulator. PMID- 27618216 TI - Functional Impairment in Miro Degradation and Mitophagy Is a Shared Feature in Familial and Sporadic Parkinson's Disease. AB - Mitochondrial movements are tightly controlled to maintain energy homeostasis and prevent oxidative stress. Miro is an outer mitochondrial membrane protein that anchors mitochondria to microtubule motors and is removed to stop mitochondrial motility as an early step in the clearance of dysfunctional mitochondria. Here, using human induced pluripotent stem cell (iPSC)-derived neurons and other complementary models, we build on a previous connection of Parkinson's disease (PD)-linked PINK1 and Parkin to Miro by showing that a third PD-related protein, LRRK2, promotes Miro removal by forming a complex with Miro. Pathogenic LRRK2G2019S disrupts this function, delaying the arrest of damaged mitochondria and consequently slowing the initiation of mitophagy. Remarkably, partial reduction of Miro levels in LRRK2G2019S human neuron and Drosophila PD models rescues neurodegeneration. Miro degradation and mitochondrial motility are also impaired in sporadic PD patients. We reveal that prolonged retention of Miro, and the downstream consequences that ensue, may constitute a central component of PD pathogenesis. PMID- 27618217 TI - Glycolytic Metabolism Plays a Functional Role in Regulating Human Pluripotent Stem Cell State. AB - The rate of glycolytic metabolism changes during differentiation of human embryonic stem cells (hESCs) and reprogramming of somatic cells to pluripotency. However, the functional contribution of glycolytic metabolism to the pluripotent state is unclear. Here we show that naive hESCs exhibit increased glycolytic flux, MYC transcriptional activity, and nuclear N-MYC localization relative to primed hESCs. This status is consistent with the inner cell mass of human blastocysts, where MYC transcriptional activity is higher than in primed hESCs and nuclear N-MYC levels are elevated. Reduction of glycolysis decreases self renewal of naive hESCs and feeder-free primed hESCs, but not primed hESCs grown in feeder-supported conditions. Reduction of glycolysis in feeder-free primed hESCs also enhances neural specification. These findings reveal associations between glycolytic metabolism and human naive pluripotency and differences in the metabolism of feeder-/feeder-free cultured hESCs. They may also suggest methods for regulating self-renewal and initial cell fate specification of hESCs. PMID- 27618220 TI - Ozone Therapy and Its Use in Medicine: Dr. Jekyll or Mr. Hyde? PMID- 27618221 TI - What's in a Context? Tenses and Tensions in Evidence-Based Medicine. PMID- 27618218 TI - Adventitial MSC-like Cells Are Progenitors of Vascular Smooth Muscle Cells and Drive Vascular Calcification in Chronic Kidney Disease. AB - Mesenchymal stem cell (MSC)-like cells reside in the vascular wall, but their role in vascular regeneration and disease is poorly understood. Here, we show that Gli1+ cells located in the arterial adventitia are progenitors of vascular smooth muscle cells and contribute to neointima formation and repair after acute injury to the femoral artery. Genetic fate tracing indicates that adventitial Gli1+ MSC-like cells migrate into the media and neointima during athero- and arteriosclerosis in ApoE-/- mice with chronic kidney disease. Our data indicate that Gli1+ cells are a major source of osteoblast-like cells during calcification in the media and intima. Genetic ablation of Gli1+ cells before induction of kidney injury dramatically reduced the severity of vascular calcification. These findings implicate Gli1+ cells as critical adventitial progenitors in vascular remodeling after acute and during chronic injury and suggest that they may be relevant therapeutic targets for mitigation of vascular calcification. PMID- 27618223 TI - Neurodegenerative Disorders and Periodontal Disease: Is There a Logical Connection? PMID- 27618222 TI - Anthropologists in Global Health Experiments. AB - Can global health experiments be part of more flexible systems of knowledge generation, where different bodies of knowledge come together to provide understanding not only of the outcomes of new interventions but also of the mechanisms through which they affect people's well-being and health? Building past work in which they tried to transform how global health experiments are carried out and inspired by the articles in this special issue, the authors of this commentary argue that strategic collaboration is needed to break the hegemony of randomized controlled trials in designing global health technologies. More open-ended experiments are possible if anthropologists team up with innovative researchers in biomedicine to develop new conceptual models and to adopt novel observational techniques and 'smart' trials that incorporate ethnography to unravel complex interactions between local biologies, attributes of health systems, social infrastructures, and users' everyday lives. PMID- 27618225 TI - Programmed death ligand 1 expression in hepatocellular carcinoma: A prognostic marker and therapeutic target for liver cancer? PMID- 27618224 TI - Angiogenic Rg1 /Sr-Doped TiO2 Nanowire/Poly(Propylene Fumarate) Bone Cement Composites. AB - A new approach is provided for preparing radiopaque and angiogenic poly(propylene fumarate) (PPF) bone cements by integrating Sr-doped n-TiO2 nanowires and ginsenoside Rg1 suitable for treating osteonecrosis. High aspect ratio radiopaque TiO2 -nanowires are synthesized by strontium doping in supercritical CO2 for the first time, showing a new phase, SrTiO3 . PPF is synthesized using a transesterification method by reacting diethyl fumarate and propylene glycol, then functionalized using maleic anhydride to produce terminal carboxyl groups, which are subsequently linked to the nanowires. The strong interfacial adhesion between functionalized PPF and nanowires is examined by scanning electron microscopy, Fourier transform infrared, X-ray photoelectron spectroscopy, thermal analysis, and mechanical testing. An angiogenic modulator, ginsenoside Rg1 , is integrated into the bone cement formulation with the mechanical properties, radiopacity, drug release, and angiogenesis behavior of the formed composites explored. The results show superior radiopacity and excellent release of ginsenoside Rg1 in vitro, as well as a dose-dependent increase in the branching point numbers. The present study suggests this new methodology provides sufficient mechanical properties, radiopacity, and angiogenic activity to be suitable for cementation of necrotic bone. PMID- 27618226 TI - Physiological Profile of Male Competitive and Recreational Surfers. AB - Furness, J, Hing, W, Sheppard, JM, Newcomer, S, Schram, B, and Climstein, M. Physiological profile of male competitive and recreational surfers. J Strength Cond Res 32(2): 372-378, 2018-Surfing consists of both high- and low-intensity paddling of varying durations, using both the aerobic and anaerobic systems. Surf specific physiological studies lack adequate group sample sizes, and V[Combining Dot Above]O2peak values are yet to determine the differences between competitive and recreational surfers. The purpose of this study was therefore to provide a comprehensive physiological profile of both recreational and competitive surfers. This multisite study involved 62 male surfers, recreational (n = 47) and competitive (n = 15). Anthropometric measurements were conducted followed by dual energy x-ray absorptiometry, anaerobic testing and finally aerobic testing. V[Combining Dot Above]O2peak was significantly greater in competitive surfers than in recreational surfers (M = 40.71 +/- 3.28 vs. 31.25 +/- 6.31 ml.kg.min, p < 0.001). This was also paralleled for anaerobic power (M = 303.93 vs. 264.58 W) for competitive surfers. Arm span and lean total muscle mass was significantly (p <= 0.01) correlated with key performance variables (V[Combining Dot Above]O2peak and anaerobic power). No significant (p >= 0.05) correlations were revealed between season rank and each of the variables of interest (V[Combining Dot Above]O2peak and anaerobic power). Key performance variables (V[Combining Dot Above]O2peak and anaerobic power) are significantly higher in competitive surfers, indicating that this is both an adaptation and requirement in this cohort. This battery of physiological tests could be used as a screening tool to identify an athlete's weaknesses or strengths. Coaches and clinicians could then select appropriate training regimes to address weaknesses. PMID- 27618228 TI - Cyclic Tensile Strain Reduces TNF-alpha Induced Expression of MMP-13 by Condylar Temporomandibular Joint Cells. AB - To investigate whether the disproportionate degradation of mandibular condyle cartilage in arthritic juvenile temporomandibular joint (TMJ) is related to distinctive responses of TMJ-derived cells to tumor necrosis factor-alpha (TNF alpha), and whether mechanical loading affects this response. The effect of TNF alpha (0.1-10 ng/ml) was tested on juvenile porcine TMJ cells isolated from the condyle, fossa, and disc, grown in 3D agarose gels. Expression of anabolic and catabolic factors was quantified by RT-qPCR and/or immunohistochemistry. Condylar cells were stimulated for 12 h with TNF-alpha (10 ng/ml), followed by 8 h of 6% cyclic tensile strain, and gene expression of MMPs was quantified. TNF-alpha (10 ng/ml) reduced the expression of the matrix proteins collagen types I and II after 6 h of incubation. Aggrecan gene expression was increased in the presence of 0.1 ng/ml TNF-alpha. The fossa and disc cells responded to TNF-alpha with an increased expression of the aggrecanase ADAMTS4. TNF-alpha enhanced MMP-13 gene and protein expression only by condylar cells. Mechanical loading reduced this effect. Cells isolated from the different cartilaginous structures reacted differently to TNF-alpha. Since the disc and fossa contain a very low level of proteoglycans in comparison to the condyle, the role played by ADAMTS4 in degradation of the fossa and disc might be limited. TNF-alpha induced MMP-13 expression by condylar cells might be involved in the degradation of the juvenile condyle. Since this expression was reduced by mechanical loading, functional loading with oral physiotherapy or orthodontic activators may help to reduce the catabolic effect of TNF-alpha. J. Cell. Physiol. 232: 1287-1294, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27618227 TI - Hindbrain A2 noradrenergic neuron adenosine 5'-monophosphate-activated protein kinase activation, upstream kinase/phosphorylase protein expression, and receptivity to hormone and fuel reporters of short-term food deprivation are regulated by estradiol. AB - Estradiol (E) mitigates acute and postacute adverse effects of 12 hr-food deprivation (FD) on energy balance. Hindbrain 5'-monophosphate-activated protein kinase (AMPK) regulates hyperphagic and hypothalamic metabolic neuropeptide and norepinephrine responses to FD in an E-dependent manner. Energy-state information from AMPK-expressing hindbrain A2 noradrenergic neurons shapes neural responses to metabolic imbalance. Here we investigate the hypothesis that FD causes divergent changes in A2 AMPK activity in E- vs. oil (O)-implanted ovariectomized female rats, alongside dissimilar adjustments in circulating metabolic fuel (glucose, free fatty acids [FFA]) and energy deficit-sensitive hormone (corticosterone, glucagon, leptin) levels. FD decreased blood glucose in oil (O)- but not E-implanted ovariectomized female rats and elevated and reduced glucagon levels in O and E, respectively. FD decreased circulating leptin in O and E, but increased corticosterone and FFA concentrations in E only. Western blot analysis of laser-microdissected A2 neurons showed that glucocorticoid receptor type II and very-long-chain acyl-CoA synthetase 3 protein profiles were amplified in FD/E vs. FD/O. A2 total AMPK protein was elevated without change in activity in FD/O, whereas FD/E exhibited increased AMPK activation along with decreased upstream phosphatase expression. The catecholamine biosynthetic enzyme dopamine-beta hydroxylase (DbetaH) was increased in FD/O but not FD/E A2 cells. The data show discordance between A2 AMPK activation and glycemic responses to FD; sensor activity was refractory to glucose decrements in FD/O but augmented in FD/E despite stabilized glucose and elevated FFA levels. E-dependent amplification of AMPK activity may reflect adaptive conversion to fatty acid oxidation and/or glucocorticoid stimulation. FD augmentation of A2 DbetaH protein profiles in FD/O but not FD/E animals suggests that FD may correspondingly regulate NE synthesis vs. metabolism/release in the absence vs. presence of E. Mechanisms underlying translation of E-contingent A2 neuron responses to FD into regulatory signaling remain to be determined. (c) 2016 Wiley Periodicals, Inc. PMID- 27618229 TI - Muscle Activation in World-Champion, World-Class, and National Breaststroke Swimmers. AB - PURPOSE: To investigate the muscle-activation patterns and coactivation with the support of kinematics in some of the world's best breaststrokers and identify performance discriminants related to national elites at maximal effort. METHODS: Surface electromyography was collected in 8 muscles from 4 world-class (including 2 world champions) and 4 national elite breaststroke swimmers during a 25-m breaststroke at maximal effort. RESULTS: World-class spent less time during the leg recovery (P = .043), began this phase with a smaller knee angle (154.6 degrees vs 161.8 degrees ), and had a higher median velocity of 0.18 m/s during the leg glide than national elites. Compared with national elites, world-class swimmers showed a difference in the muscle-activation patterns for all 8 muscles. In the leg-propulsion phase, there was less triceps brachii activation (1 swimmer 6% vs median 23.0% [8.8]). In the leg-glide phase, there was activation in rectus femoris and gastrocnemius during the beginning of this phase (all world-class vs only 1 national elite) and a longer activation in pectoralis major (world champions 71% [0.5] vs 50.0 [4.3]) (propulsive phase of the arms). In the leg recovery phase, there was more activation in biceps femoris (50.0% [15.0] vs 20.0% [14.0]) and a later and quicker activation in tibialis anterior (40.0% [7.8] vs 52.0% [6.0]). In the stroke cycle, there was no coactivation in tibialis anterior and gastrocnemius for world champions. CONCLUSION: These components are important performance discriminants. They can be used to improve muscle activation patterns and kinematics through the different breaststroke phases. Furthermore, they can be used as focus points for teaching breaststroke to beginners. PMID- 27618230 TI - Viscoelastic Properties of Human Tracheal Tissues. AB - The physiological performance of trachea is highly dependent on its mechanical behavior, and therefore, the mechanical properties of its components. Mechanical characterization of trachea is key to succeed in new treatments such as tissue engineering, which requires the utilization of scaffolds which are mechanically compatible with the native human trachea. In this study, after isolating human trachea samples from brain-dead cases and proper storage, we assessed the viscoelastic properties of tracheal cartilage, smooth muscle, and connective tissue based on stress relaxation tests (at 5% and 10% strains for cartilage and 20%, 30%, and 40% for smooth muscle and connective tissue). After investigation of viscoelastic linearity, constitutive models including Prony series for linear viscoelasticity and quasi-linear viscoelastic, modified superposition, and Schapery models for nonlinear viscoelasticity were fitted to the experimental data to find the best model for each tissue. We also investigated the effect of age on the viscoelastic behavior of tracheal tissues. Based on the results, all three tissues exhibited a (nonsignificant) decrease in relaxation rate with increasing the strain, indicating viscoelastic nonlinearity which was most evident for cartilage and with the least effect for connective tissue. The three term Prony model was selected for describing the linear viscoelasticity. Among different models, the modified superposition model was best able to capture the relaxation behavior of the three tracheal components. We observed a general (but not significant) stiffening of tracheal cartilage and connective tissue with aging. No change in the stress relaxation percentage with aging was observed. The results of this study may be useful in the design and fabrication of tracheal tissue engineering scaffolds. PMID- 27271872 TI - Effects of Treatment of Asymptomatic Hyperuricemia on Graft Survival and Mortality in Kidney Transplant Recipients. AB - BACKGROUND Hyperuricemia is very common after renal transplantation. It is associated with an increased risk of cardiovascular events and graft loss. To date, however, treatment is only recommended in symptomatic disease. MATERIAL AND METHODS We included 503 adult patients who underwent kidney transplantation at the Charite-Universitatsmedizin Berlin in this retrospective study. Patients were followed up for up to 120 months. All-cause mortality, graft survival, changes in level of serum uric acid (SUA), and estimated glomerular filtration rate (eGFR) were analyzed. RESULTS At 12 months post-transplantation, 225 patients had a serum uric acid (SUA) level >7 mg/dl: 52 patients were treated with allopurinol, 37 with benzbromarone, and 136 patients received no medication for hyperuricemia (control). At 12 months, eGFR did not differ between groups (p=0.15) but treated patients had higher SUA levels (p<0.001) compared to the control group. SUA lowering treatment was associated with a lower risk of all-cause mortality (p=0.013) and graft loss (p=0.014) compared to controls. At 120 months, patients in the treatment group had lower SUA levels (p=0.001) and higher eGFR (p<0.001) compared to the control group. CONCLUSIONS Treatment of asymptomatic hyperuricemia was associated with a substantial benefit in patient and graft survival. PMID- 27618231 TI - Pretreatment of donor islets with papain improves allograft survival without systemic immunosuppression in mice. AB - Although current immunosuppression protocols improve the efficacy of clinical allogenic islet transplantation, T cell-mediated allorejection remains unresolved, and major histocompatibility complexes (MHCs) play a crucial role in this process. Papain, a cysteine protease, has the unique ability to cleave the extracellular domain of the MHC class I structure. We hypothesized that pretreatment of donor islets with papain would diminish the expression of MHC class I on islets, reducing allograft immunogenicity and contributing to prolongation of islet allograft survival. BALB/c islets pretreated with papain were transplanted into C57BL/6J mice as an acute allorejection model. Treatment with 1 mg/mL papain significantly prolonged islet allograft survival. In vitro, to determine the inhibitory effect on T cell-mediated alloreactions, we performed lymphocyte proliferation assays and mixed lymphocyte reactions. Host T cell activation against allogenic islet cells was remarkably suppressed by pretreatment of donor islet cells with 10 mg/mL papain. Flow cytometric analysis was also performed to investigate the effect of papain treatment on the expression of MHC class I on islets. One or 10 mg/mL papain treatment reduced MHC class I expression on the islet cell surface. Pretreatment of donor islets with papain suppresses MHC class I-mediated allograft rejection in mice and contributes to prolongation of islet allograft survival without administration of systemic immunosuppressants. These results suggest that pretreatment of human donor islets with papain may reduce the immunogenicity of the donor islets and minimize the dosage of systemic immunosuppressants required in a clinical setting. PMID- 27618233 TI - ACSM Clinician Profile. PMID- 27618234 TI - Fighting Muscle Cramps With Two Spices and One Hot Fruit. PMID- 27618236 TI - Elbow Injury in the Throwing Athlete. PMID- 27618237 TI - Clinical Pearl Procedure: Reducing an Anterior Shoulder Dislocation on the Sideline. PMID- 27618238 TI - National Collegiate Athletic Association Football and Conditioning Deaths-A Positive Progress Report. PMID- 27618239 TI - Subspine Hip Impingement: An Unusual Cause of Hip Pain in an Elite Weightlifter. AB - Anterior hip pain can be difficult to diagnose due to the many pathologies and overlapping pain patterns that exist in the hip region. Clinical findings of pain at the anterior inferior iliac spine with passive hip flexion, proximal quadriceps pain and weakness, and painful impingement tests of the hip may be indicative of subspine hip impingement. This report describes the diagnosis and treatment of anterior hip pain, including subspine impingement and femoroacetabular impingement in an elite weightlifter. This case also describes how with the correct diagnosis and treatment, the athlete returned to play to her previous level of sport 11 months after a complex hip injury. PMID- 27618240 TI - Muscular Calf Injuries in Runners. AB - Calf pain is a common complaint among runners of all ages but is most frequent in masters athletes. This article focuses on injuries to the triceps surae or true 'calf muscles.' The most common calf injury is a tear of the medial gastrocnemius muscle (Tennis Leg) but other structures including the lateral gastrocnemius, plantaris and soleus also may be the cause of muscular pain. This article looks at the presentation, evaluation, and treatment of these injuries. We also highlight some examples of musculoskeletal ultrasound which is a valuable tool for rapid diagnosis of the cause and extent of injury. PMID- 27618241 TI - Elbow Injuries in the Young Throwing Athlete. AB - Baseball pitchers and other throwing athletes place their elbows under tremendous stresses, making them vulnerable to a number of unique injuries. Skeletally immature throwers in particular are at a greater risk for growth plate and other bony injuries, due to the relative strengths of these tissues and the kinematics involved in throwing. Care should be taken to fully evaluate these injuries based on the particular history and presentation to properly direct treatment and rehabilitation. Patients, as well as other athletes, coaches, and families, also should be made aware of the significant risk factors for these injuries, especially those regarding pitch limits, proper mechanics, and sufficient rest. PMID- 27618242 TI - Etiological Foundation for Practical Strategies to Prevent Exercise-Related Foot Blisters. AB - This work outlines the etiological factors for exercise-related foot blisters and the pertinent prevention strategies related to these causes. Blisters result from shear forces within the epidermis causing cell necrosis. The extent of skin shear is influenced by friction at the skin and other interfaces, various skin characteristics, bony movement, and the shear modulus of the foot ware. The number of shear cycles is another factor in the development of blisters. Key preventative strategies include limiting the number of shear cycles, avoiding moisture and particulate accumulation next to the skin, frequent use of skin lubricants, elimination of pressure points through proper fitting and broken in shoes and callous removal, use of low shear modulus insoles, and induction of skin adaptations through proper training. Other methods requiring further research, but with theoretical support, include the use of taping and low friction patches over high-friction areas, and double-layered or toe socks. PMID- 27618243 TI - Softball Pitching and Injury. AB - The windmill softball pitch generates considerable forces about the athlete's shoulder and elbow. The injury pattern of softball pitchers seems to be primarily overuse injury, and they seem not to suffer the same volume of injury that baseball pitchers do. This article will explore softball pitching techniques, kinetics and kinematics of the windmill pitch, epidemiology of softball pitchers, and discuss possible etiologies of softball pitching injuries. PMID- 27618244 TI - Development and Prevention of Running-Related Osteoarthritis. AB - Studies investigating the effect of running on risk for developing osteoarthritis at weight-bearing joints have reported with conflicting results. Generally, moderate-level running is not likely detrimental to joint health. However, many factors may be associated with the increased risk of developing osteoarthritis in runners. Factors often implicated in the development of osteoarthritis comprise those that increase joint vulnerability and those which increase joint loading. It is therefore suggested that running has different effects on different people. Efforts should be made to identify those with joint vulnerability and joint loading, and measures should be taken to have those factors and/or their running programs modified to run safely. Further investigations are needed to examine the effect of running on joint health under different conditions to confirm the association between exposure to risk factors and development of osteoarthritis, as well as to validate the effectiveness of measures for preventing running related osteoarthritis. PMID- 27618245 TI - Two-Dimensional Video Analysis of Youth and Adolescent Pitching Biomechanics: A Tool For the Common Athlete. AB - Three-dimensional (3D) motion analysis is the gold standard for analyzing the biomechanics of the baseball pitching motion. Historically, 3D analysis has been available primarily to elite athletes, requiring advanced cameras, and sophisticated facilities with expensive software. The advent of newer technology, and increased affordability of video recording devices, and smartphone/tablet based applications has led to increased access to this technology for youth/amateur athletes and sports medicine professionals. Two-dimensional (2D) video analysis is an emerging tool for the kinematic assessment and observational measurement of pitching biomechanics. It is important for providers, coaches, and players to be aware of this technology, its application in identifying causes of arm pain and preventing injury, as well as its limitations. This review provides an in-depth assessment of 2D video analysis studies for pitching, a direct comparison of 2D video versus 3D motion analysis, and a practical introduction to assessing pitching biomechanics using 2D video analysis. PMID- 27618246 TI - AMSSM Position Statement on Cardiovascular Preparticipation Screening in Athletes: Current Evidence, Knowledge Gaps, Recommendations and Future Directions. AB - Cardiovascular screening in young athletes is widely recommended and routinely performed prior to participation in competitive sports. While there is general agreement that early detection of cardiac conditions at risk for sudden cardiac arrest and death (SCA/D) is an important objective, the optimal strategy for cardiovascular screening in athletes remains an issue of considerable debate. At the center of the controversy is the addition of a resting electrocardiogram (ECG) to the standard preparticipation evaluation using history and physical examination. The American Medical Society for Sports Medicine (AMSSM) formed a task force to address the current evidence and knowledge gaps regarding preparticipation cardiovascular screening in athletes from the perspective of a primary care sports medicine physician. The absence of definitive outcomes-based evidence at this time precludes AMSSM from endorsing any single or universal cardiovascular screening strategy for all athletes, including legislative mandates. This statement presents a new paradigm to assist the individual physician in assessing the most appropriate cardiovascular screening strategy unique to their athlete population, community needs, and resources. The decision to implement a cardiovascular screening program, with or without the addition of ECG, necessitates careful consideration of the risk of SCA/D in the targeted population and the availability of cardiology resources and infrastructure. Importantly, it is the individual physician's assessment in the context of an emerging evidence-base that the chosen model for early detection of cardiac disorders in the specific population provides greater benefit than harm. AMSSM is committed to advancing evidenced-based research and educational initiatives that will validate and promote the most efficacious strategies to foster safe sport participation and reduce SCA/D in athletes. PMID- 27618247 TI - Model Building of Antibody-Antigen Complex Structures Using GBSA Scores. AB - Structure prediction of antibody-antigen complexes, which involves molecular docking to generate decoys that are ranked using a scoring function, is an important approach in the design of antibody drugs and biosensors. However, it is not easy to evaluate the stability of protein-protein complexes, using a single scoring function. Here, we developed a prediction method of antibody-antigen complex structures using the docking engine "surFit" and a scoring function (GBSA score) that combined the generalized Born (GB) energy and the hydration energy based on the solvent-accessible surface area (SA). We chose 95 antibody-antigen structural datasets for self-docking and generated many decoy structures using the surFit program. The GBSA scores were computed for all of the decoys, and the area under the curve (AUC) of the GBSA scores yielded a higher value (0.972) than the values obtained by the original surFit scores (0.873) and the ZRANK scores (0.953). To improve the accuracy of prediction, molecular dynamics (MD) simulations were performed for several decoy structures that had good GBSA scores. Consequently, average GBSA scores from MD trajectories can reduce the number of non-native decoys that have GBSA scores competitive with the near native ones. PMID- 27618248 TI - Effect of Retraining Approach-Avoidance Tendencies on an Exercise Task: A Randomized Controlled Trial. AB - BACKGROUND: Promoting regular physical activity (PA) and lessening sedentary behaviors (SB) constitute a public health priority. Recent evidence suggests that PA and SB are not only related to reflective processes (eg, behavioral intentions), but also to impulsive approach-avoidance tendencies (IAAT). This study aims to test the effect of a computerized IAAT intervention on an exercise task. METHODS: Participants (N = 115) were randomly assigned to 1 of 3 experimental conditions, in which they were either trained to approach PA and avoid SB (ApPA-AvSB condition), to approach SB and avoid PA (ApSB-AvPA condition), or to approach and avoid PA and SB equally often (active control condition). The main outcome variable was the time spent carrying out a moderate intensity exercise task. RESULTS: IAAT toward PA decreased in the ApSB-AvPA condition, tended to increase in the ApPA-AvSB condition, and remained stable in the control condition. Most importantly, the ApPA-AvSB manipulation led to more time spent exercising than the ApSB-AvPA condition. Sensitivity analyses excluding individuals who were highly physically active further revealed that participants in the ApPA-AvSB condition spent more time exercising than participants in the control condition. CONCLUSIONS: These findings provide preliminary evidence that a single intervention session can successfully change impulsive approach tendencies toward PA and can increase the time devoted to an exercise task, especially among individuals who need to be more physically active. Potential implications for health behavior theories and behavior change interventions are outlined. PMID- 27618249 TI - Quality of life and pain relief in men with metastatic castration-resistant prostate cancer on cabazitaxel: the non-interventional 'QoLiTime' study. AB - OBJECTIVE: To examine health-related quality of life (QoL) in men with metastatic castration-resistant prostate cancer (mCRPC) on cabazitaxel. PATIENTS AND METHODS: Men with mCRPC receiving cabazitaxel (25 mg/m2, every 3 weeks) and 10 mg/day oral prednis(ol)one were enrolled (2011-2014) in the non-interventional prospective 'QoLiTime' study. Primary outcome was change in QoL (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30-item) with respect to prostate-specific antigen (PSA) response after four cycles of cabazitaxel. Secondary outcomes included occurrence of adverse events (AEs). RESULTS: Of 527 men, 348 received four cycles of cabazitaxel and 266 had the necessary PSA level measurements. After four cycles, 92 (34.6%) men had a PSA level decrease >=50% (responders). QoL remained stable throughout the study (P = 0.62). Change in QoL did not differ between responders and non-responders (P = 0.69). Change in PSA level and global health status between baseline and four cycles showed an inversely proportional relationship (correlation coefficient 0.14; 95% confidence interval -0.26 to -0.01; P = 0.03), with increasing PSA level corresponding to lower health status. Responders showed no change in physical functioning vs baseline (-1.75, P = 0.12); non-responders showed a reduction vs baseline (-7.00, P < 0.001) and responders (P = 0.05). Responders showed an improvement in pain vs baseline (-7.61, P = 0.05) and vs non-responders (P = 0.01). AEs occurred in 292 patients (55.4%), most commonly anaemia (16.5%), fatigue (12.3%) and diarrhoea (11.8%). Neutropenia and febrile neutropenia were reported in 3.8% and 3.6% of patients, respectively. CONCLUSION: Prostate specific antigen level response was associated with stable physical functioning and improvement in pain. Symptom increases were seen in areas typical of chemotoxicity, but QoL was maintained. PMID- 27618251 TI - Dynamic Ellipsometric Porosimetry Investigation of Permeation Pathways in Moisture Barrier Layers on Polymers. AB - The quality assessment of moisture permeation barrier layers needs to include both water permeation pathways, namely through bulk nanoporosity and local macroscale defects. Ellipsometric porosimetry (EP) has been already demonstrated a valuable tool for the identification of nanoporosity in inorganic thin film barriers, but the intrinsic lack of sensitivity toward the detection of macroscale defects prevents the overall barrier characterization. In this contribution, dynamic EP measurements are reported and shown to be sensitive to the detection of macroscale defects in SiO2 layers on polyethylene naphthalate substrate. In detail, the infiltration of probe molecules, leading to changes in optical properties of the polymeric substrate, is followed in time and related to permeation through macroscale defects. PMID- 27618253 TI - Mechanical Thrombectomy for Stroke: How Distal Can We Go? PMID- 27618250 TI - An Inherited Genetic Variant in CEP72 Promoter Predisposes to Vincristine-Induced Peripheral Neuropathy in Adults With Acute Lymphoblastic Leukemia. AB - Peripheral neuropathy is a major toxicity of vincristine, yet no strategies exist for identifying adult patients at high-risk. We used a case-control design of 48 adults receiving protocol therapy for acute lymphoblastic leukemia (ALL) who developed vincristine-induced neuropathy (NCI grade 2-4) during treatment, and 48 matched controls who did not develop grade 2-4 neuropathy. Peripheral neuropathy was prospectively graded by National Cancer Institute (NCI) criteria. CEP72 promoter genotype (rs924607) was determined using polymerase chain reaction (PCR) based single nucleotide polymorphism (SNP) genotyping. Frequency of the CEP72 T/T genotype was higher in cases (31% vs. 10%, P = 0.0221) and the incidence of vincristine-induced neuropathy (grades 2-4) was significantly higher in patients homozygous for the CEP72 T/T genotype. 75% of the 20 patients homozygous for the CEP72 T allele developed grade 2-4 neuropathy, compared to 44% of patients with CEP72 CC or CT genotype (P = 0.0221). The CEP72 polymorphism can identify adults at increased risk of vincristine-induced peripheral neuropathy. PMID- 27618254 TI - Physical therapist screening and differential diagnosis for traumatic-onset elbow pain: A case report. AB - BACKGROUND AND PURPOSE: Elbow pain can originate from many sources yet have similar signs and symptoms, thereby presenting differential diagnostic challenges. The elbow is commonly injured, thus requiring all clinicians to possess excellent diagnostic skills. CASE DESCRIPTION: A 24-year-old woman slipped and fell on her outstretched left hand, experiencing immediate elbow pain. The same day radiographs were deemed negative by her orthopedist, who referred her to physical therapy with the diagnoses of elbow sprain and contusion. Immediately after examining the patient, the physical therapist consulted with the referring orthopedist. The decision to consult was based on: the mechanism of injury, pain severity out of proportion to the referred diagnoses, significantly limited ROM, abnormal joint end feels, exquisite pain with tactile and tuning fork bony palpation, and positive elbow extension test. OUTCOMES: The treating physical therapist shared the above-noted findings with the orthopedist, who overruled and recommended continuing the original prescription of non-steroidal anti-inflammatory medication and physical therapist treatment for four weeks. The physical therapist's updated plan of care at four weeks noted the patient's continued reports of pain, functional limitations, and disability. A magnetic resonance image (MRI) was then ordered, revealing a radial head fracture. DISCUSSION: A thorough history and examination by the physical therapist led to clustering of signs and symptoms, allowing for the development of a differential diagnosis list which included occult radial head fracture. All clinicians should be prepared to screen for complex conditions. Timely diagnosis and improved outcomes for clinically complex patients are increasingly necessary in contemporary healthcare reimbursement models. PMID- 27618255 TI - Pair correlation microscopy reveals the role of nanoparticle shape in intracellular transport and site of drug release. AB - Nanoparticle size, surface charge and material composition are known to affect the uptake of nanoparticles by cells. However, whether nanoparticle shape affects transport across various barriers inside the cell remains unclear. Here we used pair correlation microscopy to show that polymeric nanoparticles with different shapes but identical surface chemistries moved across the various cellular barriers at different rates, ultimately defining the site of drug release. We measured how micelles, vesicles, rods and worms entered the cell and whether they escaped from the endosomal system and had access to the nucleus via the nuclear pore complex. Rods and worms, but not micelles and vesicles, entered the nucleus by passive diffusion. Improving nuclear access, for example with a nuclear localization signal, resulted in more doxorubicin release inside the nucleus and correlated with greater cytotoxicity. Our results therefore demonstrate that drug delivery across the major cellular barrier, the nuclear envelope, is important for doxorubicin efficiency and can be achieved with appropriately shaped nanoparticles. PMID- 27618256 TI - The omega-SQUIPT as a tool to phase-engineer Josephson topological materials. AB - Multi-terminal superconducting Josephson junctions based on the proximity effect offer the opportunity to tailor non-trivial quantum states in nanoscale weak links. These structures can realize exotic topologies in several dimensions, for example, artificial topological superconductors that are able to support Majorana bound states, and pave the way to emerging quantum technologies and future quantum information schemes. Here we report the realization of a three-terminal Josephson interferometer based on a proximized nanosized weak link. Our tunnelling spectroscopy measurements reveal transitions between gapped (that is, insulating) and gapless (conducting) states that are controlled by the phase configuration of the three superconducting leads connected to the junction. We demonstrate the topological nature of these transitions: a gapless state necessarily occurs between two gapped states of different topological indices, in much the same way that the interface between two insulators of different topologies is necessarily conducting. The topological numbers that characterize such gapped states are given by superconducting phase windings over the two loops that form the Josephson interferometer. As these gapped states cannot be transformed to one another continuously without passing through a gapless condition, they are topologically protected. The same behaviour is found for all of the points of the weak link, confirming that this topology is a non-local property. Our observation of the gapless state is pivotal for enabling phase engineering of different and more sophisticated artificial topological materials. PMID- 27618257 TI - Quantifying losses and thermodynamic limits in nanophotonic solar cells. AB - Nanophotonic engineering shows great potential for photovoltaics: the record conversion efficiencies of nanowire solar cells are increasing rapidly and the record open-circuit voltages are becoming comparable to the records for planar equivalents. Furthermore, it has been suggested that certain nanophotonic effects can reduce costs and increase efficiencies with respect to planar solar cells. These effects are particularly pronounced in single-nanowire devices, where two out of the three dimensions are subwavelength. Single-nanowire devices thus provide an ideal platform to study how nanophotonics affects photovoltaics. However, for these devices the standard definition of power conversion efficiency no longer applies, because the nanowire can absorb light from an area much larger than its own size. Additionally, the thermodynamic limit on the photovoltage is unknown a priori and may be very different from that of a planar solar cell. This complicates the characterization and optimization of these devices. Here, we analyse an InP single-nanowire solar cell using intrinsic metrics to place its performance on an absolute thermodynamic scale and pinpoint performance loss mechanisms. To determine these metrics we have developed an integrating sphere microscopy set-up that enables simultaneous and spatially resolved quantitative absorption, internal quantum efficiency (IQE) and photoluminescence quantum yield (PLQY) measurements. For our record single-nanowire solar cell, we measure a photocurrent collection efficiency of >90% and an open-circuit voltage of 850 mV, which is 73% of the thermodynamic limit (1.16 V). PMID- 27618258 TI - Measuring broadband magnetic fields on the nanoscale using a hybrid quantum register. AB - The generation and control of fast switchable magnetic fields with large gradients on the nanoscale is of fundamental interest in material science and for a wide range of applications. However, it has not yet been possible to characterize those fields at high bandwidth with arbitrary orientations. Here, we measure the magnetic field generated by a hard-disk-drive write head with high spatial resolution and large bandwidth by coherent control of single electron and nuclear spins. We are able to derive field profiles from coherent spin Rabi oscillations close to the gigahertz range, measure magnetic field gradients on the order of 1 mT nm-1 and quantify axial and radial components of a static and dynamic magnetic field independent of its orientation. Our method paves the way for precision measurement of the magnetic fields of nanoscale write heads, which is important for future miniaturization of these devices. PMID- 27618259 TI - Removal of Nitrate by Photocatalytic Denitrification Using Nonlinear Optical Material. AB - Removal of nitrate from water has been receiving growing attention in water treatment. In this study, we report the photocatalytic denitrification (PCDN) by nonlinear optical (NLO) material, i.e. lithium niobate (LiNbO3). The hydrothermally synthesized LiNbO3 powder could achieve efficient denitrification in water, evidenced by 98.4% nitrate removal and 95.8% nitrogen selectivity at reaction time of 120 min and pH-neutral condition. Based on the first-order kinetics of PCDN, the kinetic constant for LiNbO3 is almost three times as that of conventional TiO2 (P25) under the same conditions. As suggested by the hole scavenger experiments, the LiNbO3 should proceed with photocatalytic reduction of nitrate through direct heterogeneous interaction with electrons at the conduction band of LiNbO3. This may represent a different mechanism from P25, where nitrate is mainly reduced by CO2*- radicals generated by the holes at the valence band. The unique second harmonic generation (SHG) effects of NLO materials enable them to produce more electrons and minimize the electron-hole recombination, which improves the efficiency and stability of the PCDN process. The current study provides a proof-of-concept demonstration of NLO photocatalytic material for more effective nitrate removal in water treatment. PMID- 27618260 TI - From therapeutic antibodies to chimeric antigen receptors (CARs): making better CARs based on antigen-binding domain. AB - INTRODUCTION: A variety of approaches are being pursued to improve the safety and antitumor potency of chimeric antigen receptor (CAR) T-cell therapy. However, most engineering efforts have thus far been focused on its intracellular signaling domain, while its extracellular antigen-binding domain has received less attention. Areas covered: Herein, the authors summarize the current knowledge of CAR T-cell therapy. Accordingly, they focus on its antigen-binding domain, discuss key considerations for selecting an optimal single-chain variable fragment (scFv) when designing a CAR, and suggest potential directions aimed at developing the next-generation CARs. Expert opinion: The extracellular region of CARs can play a decisive role in their safety and efficacy. Instead of directly translating an available therapeutic mAb to a scFv-based CAR construct, the authors suggest that various CAR-displayed scFvs with different affinity, specificity and binding epitopes against an individual target molecule should be generated and evaluated side-by-side. Incorporating new antibody formats that possess characteristics superior to those of scFvs may be one way to engineer safer and more effective CARs. The authors expect that further CAR engineering will enable us to target more antigens involved in hematological and solid malignancies with minimal side effects to serve unmet clinical needs. PMID- 27618261 TI - Multi-locus Analyses Reveal Four Giraffe Species Instead of One. AB - Traditionally, one giraffe species and up to eleven subspecies have been recognized [1]; however, nine subspecies are commonly accepted [2]. Even after a century of research, the distinctness of each giraffe subspecies remains unclear, and the genetic variation across their distribution range has been incompletely explored. Recent genetic studies on mtDNA have shown reciprocal monophyly of the matrilines among seven of the nine assumed subspecies [3, 4]. Moreover, until now, genetic analyses have not been applied to biparentally inherited sequence data and did not include data from all nine giraffe subspecies. We sampled natural giraffe populations from across their range in Africa, and for the first time individuals from the nominate subspecies, the Nubian giraffe, Giraffa camelopardalis camelopardalis Linnaeus 1758 [5], were included in a genetic analysis. Coalescence-based multi-locus and population genetic analyses identify at least four separate and monophyletic clades, which should be recognized as four distinct giraffe species under the genetic isolation criterion. Analyses of 190 individuals from maternal and biparental markers support these findings and further suggest subsuming Rothschild's giraffe into the Nubian giraffe, as well as Thornicroft's giraffe into the Masai giraffe [6]. A giraffe survey genome produced valuable data from microsatellites, mobile genetic elements, and accurate divergence time estimates. Our findings provide the most inclusive analysis of giraffe relationships to date and show that their genetic complexity has been underestimated, highlighting the need for greater conservation efforts for the world's tallest mammal. PMID- 27618262 TI - Sexually Antagonistic Male Signals Manipulate Germline and Soma of C. elegans Hermaphrodites. AB - Males and females pursue different reproductive strategies, which often bring them into conflict-many traits exist that benefit one sex at a cost to another [1]. Decreased female survival following mating dramatically demonstrates one aspect of this phenomenon [2-5]. Particularly intriguing is the evidence that secreted compounds can shorten lifespan of members of the opposite sex in Drosophila [6] and Caenorhabditid nematodes [7] even without copulation taking place. The purpose of such signals is not clear, however. While it is possible that they could limit subsequent mating with competitors or hasten post reproductive demise, thus decreasing competition for resources, they are also likely to harm unmated individuals. Why would a system exist that reduces the vigor of potential mates prior to mating? Addressing this question could provide insights into mechanisms and evolution of sexual conflict and reveal sensory inputs that regulate aging. Here, we describe two distinct ways in which Caenorhabditis elegans males cause faster somatic aging of hermaphrodites but also manipulate different aspects of their reproductive physiology. The first, mediated by conserved ascaroside pheromones, delays the loss of germline progenitor cells. The second accelerates development, resulting in faster sexual maturation. These signals promote male reproductive strategy and the effects harmful to hermaphrodites appear to be collateral damage rather than the goal. PMID- 27618264 TI - Knowledge-Sharing Networks in Hunter-Gatherers and the Evolution of Cumulative Culture. AB - Humans possess the unique ability for cumulative culture [1, 2]. It has been argued that hunter-gatherer's complex social structure [3-9] has facilitated the evolution of cumulative culture by allowing information exchange among large pools of individuals [10-13]. However, empirical evidence for the interaction between social structure and cultural transmission is scant [14]. Here we examine the reported co-occurrence of plant uses between individuals in dyads (which we define as their "shared knowledge" of plant uses) in BaYaka Pygmies from Congo. We studied reported uses of 33 plants of 219 individuals from four camps. We show that (1) plant uses by BaYaka fall into three main domains: medicinal, foraging, and social norms/beliefs; (2) most medicinal plants have known bioactive properties, and some are positively associated with children's BMI, suggesting that their use is adaptive; (3) knowledge of medicinal plants is mainly shared between spouses and biological and affinal kin; and (4) knowledge of plant uses associated with foraging and social norms is shared more widely among campmates, regardless of relatedness, and is important for camp-wide activities that require cooperation. Our results show the interdependence between social structure and knowledge sharing. We propose that long-term pair bonds, affinal kin recognition, exogamy, and multi-locality create ties between unrelated families, facilitating the transmission of medicinal knowledge and its fitness implications. Additionally, multi-family camps with low inter-relatedness between camp members provide a framework for the exchange of functional information related to cooperative activities beyond the family unit, such as foraging and regulation of social life. PMID- 27618263 TI - Membrane Binding by CHMP7 Coordinates ESCRT-III-Dependent Nuclear Envelope Reformation. AB - In addition to its role in membrane abscission during cytokinesis, viral budding, endosomal sorting, and plasma membrane repair [1], the endosomal sorting complex required for transport-III (ESCRT-III) machinery has recently been shown to seal holes in the reforming nuclear envelope (NE) during mitotic exit [2, 3]. ESCRT III also acts during interphase to repair the NE upon migration-induced rupture [4, 5], highlighting its key role as an orchestrator of membrane integrity at this organelle. While NE localization of ESCRT-III is dependent upon the ESCRT III component CHMP7 [3], it is unclear how this complex is able to engage nuclear membranes. Here we show that the N terminus of CHMP7 acts as a novel membrane binding module. This membrane-binding ability allows CHMP7 to bind to the ER, an organelle continuous with the NE, and it provides a platform to direct NE recruitment of ESCRT-III during mitotic exit. CHMP7's N terminus comprises tandem Winged-Helix domains [6], and, by using homology modeling and structure-function analysis, we identify point mutations that disrupt membrane binding and prevent both ER localization of CHMP7 and its subsequent enrichment at the reforming NE. These mutations also prevent assembly of downstream ESCRT-III components at the reforming NE and proper establishment of post-mitotic nucleo-cytoplasmic compartmentalization. These data identify a novel membrane-binding activity within an ESCRT-III subunit that is essential for post-mitotic nuclear regeneration. PMID- 27618265 TI - Cell Class-Lineage Analysis Reveals Sexually Dimorphic Lineage Compositions in the Drosophila Brain. AB - The morphology and physiology of neurons are directed by developmental decisions made within their lines of descent from single stem cells. Distinct stem cells may produce neurons having shared properties that define their cell class, such as the type of secreted neurotransmitter. The relationship between cell class and lineage is complex. Here we developed the transgenic cell class-lineage intersection (CLIn) system to assign cells of a particular class to specific lineages within the Drosophila brain. CLIn also enables birth-order analysis and genetic manipulation of particular cell classes arising from particular lineages. We demonstrated the power of CLIn in the context of the eight central brain type II lineages, which produce highly diverse progeny through intermediate neural progenitors. We mapped 18 dopaminergic neurons from three distinct clusters to six type II lineages that show lineage-characteristic neurite trajectories. In addition, morphologically distinct dopaminergic neurons are produced within a given lineage, and they arise in an invariant sequence. We also identified type II lineages that produce doublesex- and fruitless-expressing neurons and examined whether female-specific apoptosis in these lineages accounts for the lower number of these neurons in the female brain. Blocking apoptosis in these lineages resulted in more cells in both sexes with males still carrying more cells than females. This argues that sex-specific stem cell fate together with differential progeny apoptosis contribute to the final sexual dimorphism. PMID- 27618266 TI - Neural Representations Integrate the Current Field of View with the Remembered 360 degrees Panorama in Scene-Selective Cortex. AB - We experience our visual environment as a seamless, immersive panorama. Yet, each view is discrete and fleeting, separated by expansive eye movements and discontinuous views of our spatial surroundings. How are discrete views of a panoramic environment knit together into a broad, unified memory representation? Regions of the brain's "scene network" are well poised to integrate retinal input and memory [1]: they are visually driven [2, 3] but also densely interconnected with memory structures in the medial temporal lobe [4]. Further, these regions harbor memory signals relevant for navigation [5-8] and adapt across overlapping shifts in scene viewpoint [9, 10]. However, it is unknown whether regions of the scene network support visual memory for the panoramic environment outside of the current field of view and, further, how memory for the surrounding environment influences ongoing perception. Here, we demonstrate that specific regions of the scene network-the retrosplenial complex (RSC) and occipital place area (OPA) unite discrete views of a 360 degrees panoramic environment, both current and out of sight, in a common representational space. Further, individual scene views prime associated representations of the panoramic environment in behavior, facilitating subsequent perceptual judgments. We propose that this dynamic interplay between memory and perception plays an important role in weaving the fabric of continuous visual experience. PMID- 27618267 TI - Catastrophic Declines in Wilderness Areas Undermine Global Environment Targets. AB - Humans have altered terrestrial ecosystems for millennia [1], yet wilderness areas still remain as vital refugia where natural ecological and evolutionary processes operate with minimal human disturbance [2-4], underpinning key regional and planetary-scale functions [5, 6]. Despite the myriad values of wilderness areas-as critical strongholds for endangered biodiversity [7], for carbon storage and sequestration [8], for buffering and regulating local climates [9], and for supporting many of the world's most politically and economically marginalized communities [10]-they are almost entirely ignored in multilateral environmental agreements. This is because they are assumed to be relatively free from threatening processes and therefore are not a priority for conservation efforts [11, 12]. Here we challenge this assertion using new comparable maps of global wilderness following methods established in the original "last of the wild" analysis [13] to examine the change in extent since the early 1990s. We demonstrate alarming losses comprising one-tenth (3.3 million km2) of global wilderness areas over the last two decades, particularly in the Amazon (30%) and central Africa (14%). We assess increases in the protection of wilderness over the same time frame and show that these efforts are failing to keep pace with the rate of wilderness loss, which is nearly double the rate of protection. Our findings underscore an immediate need for international policies to recognize the vital values of wilderness and the unprecedented threats they face and to underscore urgent large-scale, multifaceted actions needed to maintain them. PMID- 27618268 TI - Bub3-Bub1 Binding to Spc7/KNL1 Toggles the Spindle Checkpoint Switch by Licensing the Interaction of Bub1 with Mad1-Mad2. AB - The spindle assembly checkpoint (SAC) ensures that sister chromatids do not separate until all chromosomes are attached to spindle microtubules and bi oriented. Spindle checkpoint proteins, including Mad1, Mad2, Mad3 (BubR1), Bub1, Bub3, and Mph1 (Mps1), are recruited to unattached and/or tensionless kinetochores. SAC activation catalyzes the conversion of soluble Mad2 (O-Mad2) into a form (C-Mad2) that binds Cdc20, BubR1, and Bub3 to form the mitotic checkpoint complex (MCC), a potent inhibitor of the anaphase-promoting complex (APC/C). SAC silencing de-represses Cdc20-APC/C activity allowing poly ubiquitination of Securin and Cyclin B, leading to the dissolution of sister chromatids and anaphase onset [1]. Understanding how microtubule interaction at kinetochores influences the timing of anaphase requires an understanding of how spindle checkpoint protein interaction with the kinetochore influences spindle checkpoint signaling. We, and others, recently showed that Mph1 (Mps1) phosphorylates multiple conserved MELT motifs in the Spc7 (Spc105/KNL1) protein to recruit Bub1, Bub3, and Mad3 (BubR1) to kinetochores [2-4]. In budding yeast, Mps1 phosphorylation of a central non-catalytic region of Bub1 promotes its association with the Mad1-Mad2 complex, although this association has not yet been detected in other organisms [5]. Here we report that multisite binding of Bub3 to the Spc7 MELT array toggles the spindle checkpoint switch by permitting Mph1 (Mps1)-dependent interaction of Bub1 with Mad1-Mad2. PMID- 27618269 TI - Long-Term Outcomes After ICU Admission Triage in Octogenarians. AB - OBJECTIVE: To describe ICU admission triage and outcomes in octogenarians. DESIGN: Multicenter prospective observational study. SETTING: Three nonuniversity hospitals and three university hospitals in Norway. PATIENTS: Patients 80 years old or older who were referred for ICU admission from November 2013 to October 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 355 included patients, 105 (29.6%) were refused ICU treatment. Risk factors for ICU refusal in patients considered "too ill/old" were advanced age and low functional status. Risk factors for ICU refusal in patients considered "too well" were advanced age, male sex, university hospital admission, comorbidity, and low Simplified Acute Physiology Score 3. Overall ICU survival was 71.6%. Hospital and 1-year survival were 56.0% and 40.0% in the ICU-admitted, 65.2% and 50.0% in the nonadmitted patients considered too well, and 32.7% and 11.5% in patients considered too ill/old, respectively. The adjusted Kaplan-Meier curves showed significantly lower survival for nonadmitted patients considered too ill/old than for ICU admitted patients and nonadmitted patients considered too well. At follow-up, triage patients had lower health-related quality of life than an age- and sex matched control group in the domains of self-care, usual care, and anxiety and depression, and a lower EuroQol visual analog scale scores. CONCLUSIONS: Overall, 29.6% of the patients were refused ICU treatment. The adjusted survival analyses showed a significantly higher survival for ICU-admitted octogenarians than for nonadmitted patients who were considered too ill/old, indicating a benefit of ICU admission. Overall, the follow-up of triage patients showed lower health-related quality of life than an age- and sex-matched control population. PMID- 27618271 TI - Methemoglobinemia Caused by Portable Dialysis in the Critically Ill. AB - OBJECTIVE: To evaluate the root cause of a series of methemoglobinemia cases in a medical ICU. RESULTS: We report a sentinel case of methemoglobinemia that was associated with dialysis sessions using a portable dialysis unit in our hospital. This led to the identification of four additional patients who developed methemoglobinemia while undergoing portable dialysis. We determined that these episodes were caused by inadequate clearance of chloramine from the tap water used for portable dialysis. Introduction of larger capacity carbon filters into the portable dialysis systems resulted in no further cases of methemoglobinemia at our institution. CONCLUSIONS: Clinicians should be aware of municipal tap water as a potential cause of methemoglobinemia and monitor for excessive levels of oxidants in dialysis water sources. The capacity of the hemodialysis equipment to clear chloramine can vary as a function of external factors. Using a reliable test method to identify chloramines in the water prior to entering the hemodialysis equipment is essential. PMID- 27618270 TI - Improving ICU-Based Palliative Care Delivery: A Multicenter, Multidisciplinary Survey of Critical Care Clinician Attitudes and Beliefs. AB - OBJECTIVE: Addressing the quality gap in ICU-based palliative care is limited by uncertainty about acceptable models of collaborative specialist and generalist care. Therefore, we characterized the attitudes of physicians and nurses about palliative care delivery in an ICU environment. DESIGN: Mixed-methods study. SETTING: Medical and surgical ICUs at three large academic hospitals. PARTICIPANTS: Three hundred three nurses, intensivists, and advanced practice providers. MEASUREMENTS AND MAIN RESULTS: Clinicians completed written surveys that assessed attitudes about specialist palliative care presence and integration into the ICU setting, as well as acceptability of 23 published palliative care prompts (triggers) for specialist consultation. Most (n = 225; 75%) reported that palliative care consultation was underutilized. Prompting consideration of eligibility for specialist consultation by electronic health record searches for triggers was most preferred (n = 123; 41%); only 17 of them (6%) felt current processes were adequate. The most acceptable specialist triggers were metastatic malignancy, unrealistic goals of care, end of life decision making, and persistent organ failure. Advanced age, length of stay, and duration of life support were the least acceptable. Screening led by either specialists or ICU teams was equally preferred. Central themes derived from qualitative analysis of 65 written responses to open-ended items included concerns about the roles of physicians and nurses, implementation, and impact on ICU team-family relationships. CONCLUSIONS: Integration of palliative care specialists in the ICU is broadly acceptable and desired. However, the most commonly used current triggers for prompting specialist consultation were among the least well accepted, while more favorable triggers are difficult to abstract from electronic health record systems. There is also disagreement about the role of ICU nurses in palliative care delivery. These findings provide important guidance to the development of collaborative care models for the ICU setting. PMID- 27618272 TI - Prognostic Factors for Long-Term Mortality in Critically Ill Patients Treated With Prolonged Mechanical Ventilation: A Systematic Review. AB - OBJECTIVES: Long-term survival for patients treated with prolonged mechanical ventilation is generally poor; however, patient-level factors associated with long-term mortality are unclear. Our objective was to systematically review the biomedical literature and synthesize data for prognostic factors that predict long-term mortality in prolonged mechanical ventilation patients. DATA SOURCES: We searched PubMed, CINAHL, and Cochrane Library from 1988 to 2015 for studies on prolonged mechanical ventilation utilizing a comprehensive strategy without language restriction. STUDY SELECTION: We included studies of adults 1) receiving mechanical ventilation for more than or equal to 14 days, 2) admitted to a ventilator weaning unit, or 3) received a tracheostomy for acute respiratory failure. We analyzed articles that used a multivariate analysis to identify patient-level factors associated with long-term mortality (>= 6 mo from when the patient met criteria for receiving prolonged mechanical ventilation). DATA EXTRACTION: We used a standardized data collection tool and assessed study quality with a customized Newcastle-Ottawa Scale. We abstracted the strength of association between each prognostic factor and long-term mortality. Individual prognostic factors were then designated as strong, moderate, weak, or inconclusive based on an a priori previously published schema. DATA SYNTHESIS: A total of 7,411 articles underwent relevance screening; 419 underwent full article review. We identified 14 articles that contained a multivariate analysis. We abstracted 19 patient-level factors that showed association with long-term mortality. Six factors demonstrated strong strength of evidence for association with the primary outcome: age, vasopressor requirement, thrombocytopenia, preexisting kidney disease, failed ventilator liberation, and acute kidney injury +/- hemodialysis requirement. All factors, except preexisting kidney disease and failed ventilator liberation, were measured at the time the patients met criteria for prolonged mechanical ventilation. CONCLUSIONS: Despite the magnitude of the public health challenge posed by the prolonged mechanical ventilation population, only 14 articles in the biomedical literature have tested patient-level factors associated with long-term mortality. Further research is needed to inform optimal patient selection for prolonged mechanical ventilation. PMID- 27618274 TI - Evaluating Pulmonary Function: An Assessment of PaO2/FIO2. AB - OBJECTIVES: PaO2/FIO2 is used commonly for diagnosis of lung injury (acute respiratory distress syndrome and transfusion-related acute lung injury), for assessment of pulmonary disease course and therapy, and in pulmonary transplantation for evaluation of donor lungs and clinical outcome. It was developed for convenience, without formal mathematical and graphic assessment to validate its suitability for these purposes. DESIGN: We examined, mathematically and graphically, the relationship of PaO2/FIO2 to FIO2 at constant normal and several degrees of increased intrapulmonary shunting (QS/QT), assessing the impact of intra- and extrapulmonary factors on the relationship and thus the reliability of PaO2/FIO2. MEASUREMENTS AND MAIN RESULTS: The relationship of PaO2/FIO2 varies at all shunt fractions but most with QS/QT from 0.1 to 0.3 with FIO2 approximately greater than 0.4. At higher QS/QT, the relationship is more constant and changes less with FIO2 more than 0.4. Hemoglobin concentration and arterial-venous oxygen content difference have large effects that can confound interpretation of PaO2/FIO2. Barometric pressure has a substantial effect; PCO2, base excess, and respiratory quotient have small effects. CONCLUSIONS: At high QS/QT with FIO2 more than 0.4, the relationship of PaO2/FIO2 to FIO2 is relatively constant. However, with QS/QT of 0.1-0.3, PaO2/FIO2 changes substantially with FIO2. Understanding the important effects of nonpulmonary factors (especially hemoglobin concentration and arterial-venous oxygen content difference) should enhance appropriate clinical use, interpretation of PaO2/FIO2, and interpretation of previous publications and future studies (especially those seeking to assess effects of anemia or transfusion on lung function). The ratio of PaO2/FIO2 is a good tool for some, but not many clinical circumstances, and is insufficiently robust for most research applications. PMID- 27618273 TI - Storytelling in the Early Bereavement Period to Reduce Emotional Distress Among Surrogates Involved in a Decision to Limit Life Support in the ICU: A Pilot Feasibility Trial. AB - OBJECTIVES: Surrogate decision makers involved in decisions to limit life support for an incapacitated patient in the ICU have high rates of adverse emotional health outcomes distinct from normal processes of grief and bereavement. Narrative self-disclosure (storytelling) reduces emotional distress after other traumatic experiences. We sought to assess the feasibility, acceptability, and tolerability of storytelling among bereaved surrogates involved in a decision to limit life support in the ICU. DESIGN: Pilot single-blind trial. SETTING: Five ICUs across three hospitals within a single health system between June 2013 and November 2014. SUBJECTS: Bereaved surrogates of ICU patients. INTERVENTIONS: Storytelling and control conditions involved printed bereavement materials and follow-up assessments. Storytelling involved a single 1- to 2-hour home or telephone visit by a trained interventionist who elicited the surrogate's story. MEASUREMENTS AND MAIN RESULTS: The primary outcomes were feasibility (rates of enrollment, intervention receipt, 3- and 6-mo follow-up), acceptability (closed and open-ended end-of-study feedback at 6 mo), and tolerability (acute mental health services referral). Of 53 eligible surrogates, 32 (60%) consented to treatment allocation. Surrogates' mean age was 55.5 (SD, 11.8), and they were making decisions for their parent (47%), spouse (28%), sibling (13%), child (3%), or other relation (8%). We allocated 14 to control and 18 to storytelling, 17 of 18 (94%) received storytelling, 14 of 14 (100%) and 13 of 14 (94%) control subjects and 16 of 18 (89%) and 17 of 18 (94%) storytelling subjects completed their 3- and 6-month telephone assessments. At 6 months, nine of 13 control participants (69%) and 16 of 17 storytelling subjects (94%) reported feeling "better" or "much better," and none felt "much worse." One control subject (8%) and one storytelling subject (6%) said that the study was burdensome, and one control subject (8%) wished they had not participated. No subjects required acute mental health services referral. CONCLUSION: A clinical trial of storytelling in this study population is feasible, acceptable, and tolerable. PMID- 27618275 TI - Suppression of T Cell Autophagy Results in Decreased Viability and Function of T Cells Through Accelerated Apoptosis in a Murine Sepsis Model. AB - OBJECTIVE: While type 1 programmed cell death (apoptosis) of T cells leads to immunosuppression in sepsis, a crosstalk between apoptosis and autophagy (type 2 programmed cell death) has not been shown. The aim of this study is to elucidate the details of the interaction between autophagy and immunosuppression. DESIGN: Laboratory investigation in the murine sepsis model. SETTING: University laboratory. SUBJECTS: Six- to 8-week-old male mice. INTERVENTIONS: We investigated the kinetics of autophagy in T cells from spleen in a cecal ligation and puncture model with green fluorescent protein-microtubule-associated protein light chain 3 transgenic mice. We analyzed apoptosis, mitochondrial homeostasis and cytokine production in T cells, and survival rate after cecal ligation and puncture using T cell-specific autophagy-deficient mice. MEASUREMENTS AND MAIN RESULTS: We observed an increase of autophagosomes, which was assessed by flow cytometry. However, an autophagy process in CD4 T cells during sepsis was insufficient including the accumulation of p62. On the other hand, a blockade of autophagy accelerated T cell apoptosis compared with the control mice, augmenting the gene expression of Bcl-2-like 11 and programmed cell death 1. Furthermore, mitochondrial accumulation in T cells occurred via a blockade of autophagy during sepsis. In addition, interleukin-10 production in CD4 T cells from the cecal ligation and puncture-operated knockout mice was markedly increased. Consequently, deficiency of autophagy in T cells significantly decreased the survival rate in the murine sepsis model. CONCLUSIONS: We demonstrated that blocking autophagy accelerated apoptosis and increased mortality in concordance with the insufficient autophagy process in CD4 T cells in the murine sepsis model, suggesting that T cell autophagy plays a protective role against apoptosis and immunosuppression in sepsis. PMID- 27618276 TI - Multiple Organ Dysfunction Score Is Superior to the Obstetric-Specific Sepsis in Obstetrics Score in Predicting Mortality in Septic Obstetric Patients. AB - OBJECTIVES: Mortality prediction scores have been used for a long time in ICUs; however, numerous studies have shown that they over-predict mortality in the obstetric population. With sepsis remaining a major cause of obstetric mortality, we aimed to look at five mortality prediction scores (one obstetric-based and four general) in the septic obstetric population and compare them to a nonobstetric septic control group. SUBJECT AND DESIGN: Women in the age group of 16-50 years with an admission diagnosis or suspicion of sepsis were included. In a multicenter obstetric population (n = 797), these included all pregnant and postpartum patients up to 6 weeks postpartum. An age- and gender-matched control nonobstetric population was drawn from a single-center general critical care population (n = 2,461). Sepsis in Obstetric Score, Acute Physiology and Chronic Health Evaluation II, Simplified Acute Physiology Score II, Sequential Organ Failure Assessment, and Multiple Organ Dysfunction Scores were all applied to patients meeting inclusion criteria in both cohorts, and their area under the receiver-operator characteristic curves was calculated to find the most accurate predictor. MEASUREMENTS AND MAIN RESULTS: A total of 146 septic patients were found for the obstetric cohort and 299 patients for the nonobstetric control cohort. The Sepsis in Obstetric Score, Acute Physiology and Chronic Health Evaluation II, Simplified Acute Physiology Score II, Sequential Organ Failure Assessment, and Multiple Organ Dysfunction Scores gave area under the receiver operator characteristic curves of 0.67, 0.68, 0.72, 0.79, and 0.84 in the obstetric cohort, respectively, and 0.64, 0.72, 0.61, 0.78, and 0.74 in the nonobstetric cohort, respectively. The Sepsis in Obstetric Score performed similarly to all the other scores with the exception of the Multiple Organ Dysfunction Score, which was significantly better (p < 0.05). CONCLUSION: The Sepsis in Obstetric Score, designed specifically for sepsis in obstetric populations, was not better than general severity of illness scoring systems. Furthermore, the Sepsis in Obstetric Score performance was no different in an obstetric sepsis population compared to a nonobstetric sepsis population. The Multiple Organ Dysfunction Score is a simple organ-based score, and this result supports the use of organ-based outcome predictors in ICU even in an obstetric sepsis population. PMID- 27618277 TI - Relative Bradycardia in Patients With Septic Shock Requiring Vasopressor Therapy. AB - OBJECTIVES: Tachycardia is common in septic shock, but many patients with septic shock are relatively bradycardic. The prevalence, determinants, and implications of relative bradycardia (heart rate, < 80 beats/min) in septic shock are unknown. To determine mortality associated with patients who are relatively bradycardic while in septic shock. DESIGN: Retrospective study of patients admitted for septic shock to study ICUs during 2005-2013. SETTING: One large academic referral hospital and two community hospitals. PATIENTS: Adult patients with septic shock requiring vasopressors. INTERVENTION: None. MEASUREMENTS: Primary outcome was 28 day mortality. We used multivariate logistic regression to evaluate the association between relative bradycardia and mortality, controlling for confounding with inverse probability treatment weighting using a propensity score. RESULTS: We identified 1,554 patients with septic shock, of whom 686 (44%) met criteria for relative bradycardia at some time. Twenty-eight-day mortality in this group was 21% compared to 34% in the never-bradycardic group (p < 0.001). Relatively bradycardic patients were older (65 vs 60 yr; p < 0.001) and had slightly lower illness severity (Sequential Organ Failure Assessment, 10 vs 11; p = 0.004; and Acute Physiology and Chronic Health Evaluation II, 27 vs 28; p = 0.008). After inverse probability treatment weighting, covariates were balanced, and the association between relative bradycardia and survival persisted (p < 0.001). CONCLUSIONS: Relative bradycardia in patients with septic shock is associated with lower mortality, even after adjustment for confounding. Our data support expanded investigation into whether inducing relative bradycardia will benefit patients with septic shock. PMID- 27618280 TI - Biocompatible astaxanthin as novel contrast agent for biomedical imaging. AB - Photoacoustic imaging (PAI) is a hybrid imaging modality with high resolution and sensitivity that can be beneficial for cancer staging. Due to insufficient endogenous photoacoustic (PA) contrast, the development of exogenous agents is critical in targeting cancerous tumors. The current study demonstrates the feasibility of marine-oriented material, astaxanthin, as a biocompatible PA contrast agent. Both silicon tubing phantoms and ex vivo bladder tissues are tested at various concentrations (up to 5 mg/ml) of astaxanthin to quantitatively explore variations in PA responses. A Q-switched Nd : YAG laser (lambda = 532 nm) in conjunction with a 5 MHz ultrasound transducer is employed to generate and acquire PA signals from the samples. The phantom results presented that the PA signal amplitudes increase linearly with the astaxanthin concentrations (threshold detection = 0.31 mg/ml). The tissue injected with astaxanthin yields up to 16-fold higher PA signals, compared with that with saline. Due to distribution of the injected astaxanthin, PAI can image the margin of astaxanthin boles as well as quantify their volume in 3D reconstruction. Further investigations on selective tumor targeting are required to validate astaxanthin as a potential biocompatible contrast agent for PAI-assisted bladder cancer detection. PMID- 27618278 TI - The neurobiology of self-face recognition in depressed adolescents with low or high suicidality. AB - This study sought to test whether the neurobiology of self-processing differentiated depressed adolescents with high suicidality (HS) from those with low suicidality (LS) and healthy controls (HC; N = 119, MAGE = 14.79, SD = 1.64, Min = 11.3, Max = 17.8). Participants completed a visual self-recognition task in the scanner during which they identified their own or an unfamiliar adolescent face across 3 emotional expressions (happy, neutral or sad). A 3-group (HS, LS, HC) by 2 within-subject factors (2 Self conditions [self, other] and 3 Emotions [happy, neutral, sad]) GLM yielded (a) a main effect of Self condition with all participants showing higher activity in the right occipital, precuneus and fusiform during the self- versus other-face conditions; (b) a main effect of Group where all depressed youth showed higher dorsolateral prefrontal cortex activity than HC across all conditions, and with HS showing higher cuneus and occipital activity versus both LS and HC; and (c) a Group by Self by Emotion interaction with HS showing lower activity in both mid parietal, limbic, and prefrontal areas in the Happy self versus other-face condition relative to the LS group, who in turn had less activity compared to HC youth. Covarying for depression severity replicated all results except the third finding; In this subsequent analysis, a Group by Self interaction showed that although HC had similar midline cortical structure (MCS) activity for all faces, LS showed higher MCS activity for the self versus other faces, whereas HS showed the opposite pattern. Results suggest that the neurophysiology of emotionally charged self referential information can distinguish depressed, suicidal youth versus nonsuicidal depressed and healthy adolescents. Neurophysiological differences and implications for the prediction of suicidality in youth are discussed. (PsycINFO Database Record PMID- 27618281 TI - Effectiveness of alitretinoin in severe chronic hand eczema: PASSION, a real world observational study. AB - PURPOSE: Severe chronic hand eczema (CHE) has a debilitating effect on quality of life (QoL). PASSION evaluated the effectiveness of oral alitretinoin on QoL and work productivity in patients with severe CHE following prescribing guidelines. METHODS: A non-interventional, open-label, observational, multicentre study conducted in Germany in fulfilment of German guidelines. Patients (n = 631) were treated with once-daily alitretinoin for <=24 weeks under standard daily practise conditions. Effectiveness was assessed by Physician Global Assessment (PGA), QoL Assessment (EQ-5D) and work impairment. Tolerability and safety were assessed by adverse event (AE) monitoring. RESULTS: In total, 279 (44.2%) patients dropped out before Week 24. Of the 631 patients enrolled, 29.8% achieved a PGA rating of clear/almost clear at Week 24. Mean (standard deviation) EQ-5D utility and EQ-5D visual analogue scale scores at baseline were 0.76 (0.25) and 53.6 (23.55), respectively, and increased to 0.94 (0.12) and 80.8 (19.23) at Week 24, indicating improved QoL. At baseline, 49.4%/29.1% of patients reported strong/very strong workplace impairment, respectively, and decreased to 8.5%/1.4%, respectively, at Week 24. AEs were reported in 116 (18.4%) patients. No new safety signals were observed. CONCLUSIONS: Alitretinoin produced marked improvement in the QoL and work productivity of patients with severe CHE. PMID- 27618279 TI - Transdiagnostic neural markers of emotion-cognition interaction in psychotic disorders. AB - Deficits in working memory (WM) and emotion processing are prominent impairments in psychotic disorders, and have been linked to reduced quality of life and real world functioning. Translation of knowledge regarding the neural circuitry implementing these deficits into improved diagnosis and targeted treatments has been slow, possibly because of categorical definitions of disorders. Using the dimensional Research Domain Criteria (RDoC) framework, we investigated the clinical and practical utility of transdiagnostic behavioral and neural measures of emotion-related WM disruption across psychotic disorders. Behavioral and functional MRI data were recorded while 53 participants with psychotic disorders and 29 participants with no history of psychosis performed a modified n-back task with fear and neutral distractors. Hierarchical regression analyses showed that psychotic symptoms entered after diagnosis accounted for unique variance in fear versus neutral accuracy and activation in the ventrolateral, dorsolateral, and dorsomedial prefrontal cortex, but diagnostic group entered after psychotic symptoms did not. These results remained even after controlling for negative symptoms, disorganized symptoms, and dysphoria. Finally, worse accuracy and greater prefrontal activity were associated with poorer social functioning and unemployment across diagnostic groups. Present results support the transdiagnostic nature of behavioral and neuroimaging measures of emotion-related WM disruption as they relate to psychotic symptoms, irrespective of diagnosis. They also provide support for the practical utility of these markers in explaining real-world functioning. Overall, these results elucidate key aspects of the RDoC construct of WM maintenance by clarifying its transdiagnostic importance and clinical utility in psychotic disorders. (PsycINFO Database Record PMID- 27618283 TI - Investigation into the Surface Chemistry of Li4Ti5O12 Nanoparticles for Lithium Ion Batteries. AB - Elucidating surface chemistry of Li4Ti5O12 anode material plays a critical role in solving gas evolution in Li4Ti5O12-based lithium ion batteries. Herein, we propose a CO2 cycloaddition reaction to study the surface chemistry of Li4Ti5O12 nanoparticles. Through the reaction, bare Li4Ti5O12 nanoparticles were demonstrated to have extensive Lewis-acid sites, that is, dangling Ti bonds or hydroxyl groups. Lewis-acid site is considered to be able to initiate the decomposition of electrolyte solvents and may also serve as one of the main reasons for gas evolution. TiNx coating layer is used to cover up the Lewis-acid site and is able to decrease yield of the cycloaddition reaction to some extent. These findings may provide a simple yet very effective way to evaluate surface chemistry and gas evolution in other lithium ion batteries, not limited to Li4Ti5O12-based batteries. PMID- 27618284 TI - Financial Loss for Inpatient Care of Medicaid-Insured Children. AB - Importance: Medicaid payments tend to be less than the cost of care. Federal Disproportionate Share Hospital (DSH) payments help hospitals recover such uncompensated costs of Medicaid-insured and uninsured patients. The Patient Protection and Affordable Care Act reduces DSH payments in anticipation of fewer uninsured patients and therefore decreased uncompensated care. However, unlike adults, few hospitalized children are uninsured, while many have Medicaid coverage. Therefore, DSH payment reductions may expose extensive Medicaid financial losses for hospitals serving large absolute numbers of children. Objectives: To identify types of hospitals with the highest Medicaid losses from pediatric inpatient care and to estimate the proportion of losses recovered through DSH payments. Design, Setting, and Participants: This retrospective cross sectional analysis evaluated Medicaid-insured hospital discharges of patients 20 years and younger from 23 states in the 2009 Kids' Inpatient Database. The dates of the analysis were March to September 2015. Hospitals were categorized as freestanding children's hospitals (FSCHs), children's hospitals within general hospitals, non-children's hospital teaching hospitals, and non-children's hospital nonteaching hospitals. Financial records of FSCHs in the data set were used to estimate the proportion of Medicaid losses recovered through DSH payments. Main Outcomes and Measures: Hospital financial losses from inpatient care of Medicaid-insured children (defined as the reimbursement minus the cost of care) were compared across hospital types. For our subsample of FSCHs, Medicaid insured inpatient financial losses were calculated with and without each hospital's DSH payment. Results: The 2009 Kids' Inpatient Database study population included 1485 hospitals and 843 725 Medicaid-insured discharges. Freestanding children's hospitals had a higher median number of Medicaid-insured discharges (4082; interquartile range [IQR], 3524-5213) vs non-children's hospital teaching hospitals (674; IQR, 258-1414) and non-children's hospital nonteaching hospitals (161; IQR, 41-420). Freestanding children's hospitals had the largest median Medicaid losses from pediatric inpatient care (-$9 722 367; IQR, -$16 248 369 to -$2 137 902). Smaller losses were experienced by non children's hospital teaching hospitals (-$204 100; IQR, -$1 014 100 to $14 700]) and non-children's hospital nonteaching hospitals (-$28 310; IQR, -$152 370 to $9040]). Disproportionate Share Hospital payments to FSCHs reduced their Medicaid losses by almost half. Conclusions and Relevance: Estimated financial losses from pediatric inpatients covered by Medicaid were much larger for FSCHs than for other hospital types. For children's hospitals, small anticipated increases in insured children are unlikely to offset the reductions in DSH payments. PMID- 27618285 TI - Item analyses of memory differences. AB - OBJECTIVE: Although performance on memory and other cognitive tests is usually assessed with a score aggregated across multiple items, potentially valuable information is also available at the level of individual items. METHOD: The current study illustrates how analyses of variance with item as one of the factors, and memorability analyses in which item accuracy in one group is plotted as a function of item accuracy in another group, can provide a more detailed characterization of the nature of group differences in memory. Data are reported for two memory tasks, word recall and story memory, across age, ability, repetition, delay, and longitudinal contrasts. RESULTS: The item-level analyses revealed evidence for largely uniform differences across items in the age, ability, and longitudinal contrasts, but differential patterns across items in the repetition contrast, and unsystematic item relations in the delay contrast. CONCLUSION: Analyses at the level of individual items have the potential to indicate the manner by which group differences in the aggregate test score are achieved. PMID- 27618282 TI - Stage-Specific Demethylation in Primordial Germ Cells Safeguards against Precocious Differentiation. AB - Remodeling DNA methylation in mammalian genomes can be global, as seen in preimplantation embryos and primordial germ cells (PGCs), or locus specific, which can regulate neighboring gene expression. In PGCs, global and locus specific DNA demethylation occur in sequential stages, with an initial global decrease in methylated cytosines (stage I) followed by a Tet methylcytosine dioxygenase (Tet)-dependent decrease in methylated cytosines that act at imprinting control regions (ICRs) and meiotic genes (stage II). The purpose of the two-stage mechanism is unclear. Here we show that Dnmt1 preserves DNA methylation through stage I at ICRs and meiotic gene promoters and is required for the pericentromeric enrichment of 5hmC. We discovered that the functional consequence of abrogating two-stage DNA demethylation in PGCs was precocious germline differentiation leading to hypogonadism and infertility. Therefore, bypassing stage-specific DNA demethylation has significant consequences for progenitor germ cell differentiation and the ability to transmit DNA from parent to offspring. PMID- 27618286 TI - l-DOPA-induced dyskinesia in Parkinson's disease: Are neuroinflammation and astrocytes key elements? AB - Inflammation in Parkinson's disease (PD) is a new concept that has gained ground due to the potential of mitigating dopaminergic neuron death by decreasing inflammation. The solution to this question is likely to be complex. We propose here that the significance of inflammation in PD may go beyond the nigral cell death. The pathological process that underlies PD requires years to reach its full extent. A growing body of evidence has been accumulated on the presence of multiple inflammatory signs in the brain of PD patients even in very late stages of the disease. Because neuron-microglia-astrocyte interactions play a major role in the plasticity of neuronal response to l-DOPA in post-synaptic neurons, we focused this review on our recent results of l-DOPA-induced dyskinesia in rodents correlating it to significant findings regarding glial cells and neuroinflammation. We showed that in the rat model of PD/l-DOPA-induced dyskinesia there was an increased expression of inflammatory markers, such as the enzymes COX2 in neurons and iNOS in glial cells, in the dopamine-denervated striatum. The gliosis commonly seem in PD was associated with modifications in astrocytes and microglia that occur after chronic treatment with l-DOPA. Either as a cause, consequence, or promoter of progression of neuronal degeneration, inflammation plays a role in PD. The key aims of current PD research ought to be to elucidate (a) the time sequence in which the inflammatory factors act in PD patient brain and (b) the mechanisms by which neuroinflammatory response contributes to the collateral effects of l-DOPA treatment. PMID- 27618288 TI - Investigation of alterations in multifractality in optical coherence tomographic images of in vivo human retina. AB - Optical coherence tomography (OCT) enables us to monitor alterations in the thickness of the retinal layer as disease progresses in the human retina. However, subtle morphological changes in the retinal layers due to early disease progression often may not lead to detectable alterations in the thickness. OCT images encode depth-dependent backscattered intensity distribution arising due to the depth distributions of the refractive index from tissue microstructures. Here, such depth-resolved refractive index variations of different retinal layers were analyzed using multifractal detrended fluctuation analysis, a special class of multiresolution analysis tools. The analysis extracted and quantified microstructural multifractal information encoded in normal as well as diseased human retinal OCT images acquired